Butenoic acid derivatives

ABSTRACT

A butenoic acid compound is defined by the following formula: ##STR1## in which Z is O,S, vinylene or azomethyne, A is an alkylene and J is phenyl or etc. It is useful to treat the heart disease.

This application is a continuation of application Ser. No. 07/518,508filed on May 3, 1990 now abandoned, the entire contents of which areincorporated herein by reference.

The present invention relates to a butenoic acid derivative having anexcellent activity as a drug.

BACKGROUND OF THE INVENTION AND PRIOR ART

In Europe and America, cardiovascular diseases top the list of deathcauses. Meanwhile, although cerebrovascular diseases such as cerebralapoplexy ranked rather high in death causes in Japan, a tendency forischemic heart diseases to increase rapidly has recently been seen asthe life-style and diet have neared those of Europe and America.

The term "ischemic heart disease" refers to a series of diseasesgenerally caused when the supply of oxygen to the cardiac muscle doesnot meet the demand of the muscle for oxygen. Representative examplesthereof include coronary arteriosclerosis, acute myocardial infarctionand stenocardia. Although a nitro drug, calcium antagonist or β-blockeris now used for the treatment of the above diseases, no sufficientlyeffective drug has been found as yet. Accordingly, the development of anew drug superior to those of the prior art has been expected.

CONSTITUTION AND EFFECT OF THE INVENTION

The inventors of the present invention have studied for a long time toobtain a new type of remedy for ischemic heart diseases and have foundthat the butenoic acid derivative which will be described below exhibitsan excellent coronary vasodilating effect.

Namely, the compound of the present invention is a butenoic acidderivative represented by the following general formula (I) or apharmacologically acceptable salt thereof ##STR2## wherein R¹ represents1 a heteroaryl group, 2 a group represented by the formula: ##STR3##{wherein R² and R^(2') may be the same or different from each other andeach represent a hydrogen atom or a lower alkyl, cycloalkyl or allylgroup, or alternatively, R² and R^(2') may together form a ring, Xrepresents an oxygen or sulfur atom, a group represented by the formula:═N--R³ (wherein R³ represents a cyano, lower alkanoyl, loweralkoxycarbonyl, carbamoyl, sulfamoyl, alkylsulfonyl, arylsulfonyl ornitro group) or a group represented by the formula: ##STR4## (wherein R'and R" may be the same or different from each other and each represent ahydrogen atom or an alkylsulfonyl, arylsulfonyl or nitro group)}, 3 agroup represented by the formula: ##STR5## {wherein R⁴ represents ahydrogen atom or a lower alkyl, cycloalkyl or allyl group and R⁵represents a cyano, lower alkylcarbonyl, lower alkoxycarbonyl, carbamoylor sulfamoyl group}, 4 or a group represented by the formula: E--NH--(wherein E represents a heteroaryl group which may be substituted),

Z represents an oxygen or sulfur atom or a vinylene (--CH═CH--) orazomethyne (--N═CH--) group,

R⁶ and R⁷ may be the same or different from each other and eachrepresent a hydrogen atom or a lower alkyl, cycloalkyl or allyl group,

A represents a C₁˜6 alkylene group which may have a lower alkyl orhydroxy-substituted lower alkyl substituent bonded to any carbon of thegroup,

J represents a group represented by the formula: ##STR6## {wherein R⁸,R⁹ and R¹⁰ may be the same or different from each other and eachrepresent a hydrogen or halogen atom, a lower-alkyl, lower alkoxy,hydroxyl, nitro, cyano or trifluoromethyl group, a group represented bythe formula: ##STR7## (wherein R¹¹ and R¹² may be the same or differentfrom each other and each represent a hydrogen atom or a lower alkylgroup) or an alkanoylamino group, or alternatively, any two membersamong R⁸, R⁹ and R¹⁰ may form an alkylenedioxy group together withadjacent carbon atoms}, and n represents an integer of 1 to 6.

In the above definition, when Z is a group represented by the formula:--CH═CH--, i.e., when the group represented by the formula: ##STR8## isa phenyl group, the compound of the present invention is a butenoic acidderivative represented by the following general formula (I'): ##STR9##wherein R¹ represents 1 a heteroaryl group, 2 a group represented by theformula: ##STR10## {wherein R² and R^(2') may be the same or differentfrom each other and each represent a hydrogen atom or a lower alkyl,cycloalkyl or allyl group, or alternatively, R² and R^(2') may togetherform a ring, X represents an oxygen or sulfur atom, a group representedby the formula: ═N--R³ (wherein R³ represents a cyano, lower alkanoyl,lower alkoxycarbonyl, carbamoyl, sulfamoyl, alkylsulfonyl, arylsulfonylor nitro group) or a group represented by the formula: ##STR11##(wherein R' and R" may be the same or different from each other and eachrepresent a hydrogen atom or an alkylsulfonyl, arylsulfonyl or nitrogroup)}, 3 a group represented by the formula: ##STR12## }wherein R⁴represents a hydrogen atom or a lower alkyl, cycloalkyl or allyl groupand R⁵ represents a cyano, lower alkylcarbonyl, lower alkoxycarbonyl,carbamoyl or sulfamoyl group}, or 4 a group represented by the formula:E--NH-- (wherein E represents a heteroaryl group which may besubstituted),

R⁶ and R⁷ may be the same or different from each other and eachrepresent a hydrogen atom or a lower alkyl, cycloalkyl or allyl group,

A represents a C₁˜6 alkylene group which may have a lower alkyl orhydroxy-substituted lower alkyl substituent bonded to any carbon of thegroup,

J represents a group represented by the formula: ##STR13## {wherein R⁸,R⁹ and R¹⁰ may be the same or different from each other and eachrepresent a hydrogen or halogen atom, a lower alkyl, lower alkoxy,hydroxyl, nitro, cyano or trifluoromethyl group, a group represented bythe formula: ##STR14## (wherein R¹¹ and R¹² may be the same or differentfrom each other and each represent a hydrogen atom or a lower alkylgroup) or an alkanoylamino group, or alternatively, any two membersamong R⁸, R⁹ and R¹⁰ may form an alkylenedioxy group together withadjacent carbon atoms}, and n represents an integer of 1 to 6.

The lower alkyl group defined with respect to R², R^(2'), R⁴, R⁶, R⁷,R⁸, R⁹, R¹⁰, R¹¹ and R¹² in the above definition of the compound (I)according to the present invention may be a C₁˜6 straight-chain orbranched alkyl group and examples thereof include methyl, ethyl,n-propyl, n-butyl, isopropyl, isobutyl, sec-butyl, n-pentyl,1-ethylpropyl, isoamyl and n-hexyl groups, among which methyl and ethylgroups are most preferred.

The lower alkoxy group defined with respect to R⁸, R⁹ and R¹⁰ may be onederived from any of the lower alkyl groups described above.

The lower alkoxycarbonyl group defined with respect to R³ and R⁵ may beone derived from any of the lower alkyl groups described above.

The heteroaryl group defined with respect to R¹ is a substituted orunsubstituted heterocyclic group. The heterocyclic group may contain oneor more nitrogen atoms. Particular examples thereof include imidazolylgroups such as 1-imidazolyl and 2-imidazolyl groups; and 3-pyridyl,4-pyridyl, 1,4-dihydro-4-oxo-1-pyridyl, 1,4-dihydro-4-oxo-2-pyridyl,1-oxy-4-pyridyl and 1,4-dihydro-4-oxo-3-pyridyl, among which1-imidazolyl, 1-oxy-4-pyridyl and 1,4-dihydro-4-oxo-1-pyridyl are mostpreferred.

These heteroaryl groups may be each one derived from a heteroaryl groupsubstituted with a lower alkyl group such as a methyl group.

As described above, a preferred example of the heteroaryl group is asubstituted or unsubstituted 1-imidazolyl group which follows: ##STR15##

In the above formula, R^(a) and R^(b) may be the same or different fromeach other and each represent a hydrogen atom, a nitro, cyano,trifluoromethyl, alkylsulfonyl or arylsulfonyl group, a halogen atom ora lower alkoxycarbonyl group.

Among them, a group represented by the formula wherein R^(a) is a4-nitro group and R^(b) is H is preferred.

The heteroaryl group defined with respect to E may be a substituted orunsubstituted heterocyclic group. Preferred examples thereof includefive or six-membered ring groups each containing one or more nitrogenatoms. These groups may be each substituted with, for example, a loweralkyl group such as methyl or a lower alkoxy group such as methoxy.Alternatively, the carbon atom constituting the ring may form a carbonylgroup together with an oxygen atom. Representative examples of such agroup include ##STR16##

R³ represents a cyano, lower alkanoyl, lower alkoxycarbonyl, carbamoyl,sulfamoyl, alkylsulfonyl, arylsulfonyl or nitro group, among which cyanogroup is most preferred.

The alkanoylamino group defined with respect to R⁸, R⁹ and R¹⁰ is onederived from any of the lower alkyl groups particularly described above.

A represents an alkylene group having 1 to 6 carbon atoms, preferably 3or 4 carbon atoms. The alkylene group may be substituted with a loweralkyl group as described above or a hydroxy-substituted lower alkylgroup (for example, a methyl or hydroxymethyl group) at any carbon ofthe alkylene group.

J represents a group represented by the formula: ##STR17## (wherein R⁸,R⁹ and R¹⁰ are each as defined above). Particularly, it is preferredthat 1 to 3 members out of R⁸, R⁹ and R¹⁰ are each a lower alkyl group,still preferably a methyl group.

In compound of the invention, that having the following formula (A) ispreferable. ##STR18##

In the formula (A), Ra and Rb are, independently of each other,hydrogen, nitro, cyano, trifluoromethyl, an alkylsulfonyl, anarylsulfonyl, a halogen or a lower alkylcarbonyl, Z is vinylene, oxygen,sulfur or azomethyne, R6 and R7 and J are the same as defined in theformula (I), A' is an alkylene having 4 to 6 carbon atoms and n is aninteger of 1 to 6.

The compound of the formula (A) having hydrogen for both Ra and Rb ismost preferable. Secondly preferable is the compound having hydrogen forRa and nitro or cyano for Rb. The vinylene for Z to form a phenyl ringis most preferable. Secondly preferable is sulfur for Z. Hydrogen or alower alkyl for R6 and R7 is preferable. Methyl is most preferable inthe alkyl. Hydrogen for R6 and methyl for R7 are most preferable. A' ispreferred to be an alkylene having 4 carbon atoms. 2 for n is mostpreferable. The phenyl for J is preferred to have a lower alkoxy having1 to 3 carbon atoms, especially methoxy, for R8, R9 and R10.3,4-dimethoxyphenyl and 3,5-dimethoxyphenyl are most preferable.

The compounds having the formulae (B), (C), (D) and (E) are preferable.All the substitutes of these formulae are defined before. ##STR19##

In the formula (C), R2 and R2' are preferably hydrogen or a lower alkylsuch as methyl. X is preferably sulfur and ═N--R3, R3 being definedbefore. R3 is preferably cyano. Z is preferably vinyl. A is preferablyan alkylene having 3 or 4 carbon atoms. m is preferably 2. J ispreferably R8, R9 and R10 having phenyl, such as 3,4-dimethoxy and3,5-dimethoxy.

The compound (D) is a preferable one of (C).

In the formula (E), K is pyridyl such as 3-pyridyl and 4-pyridyl,N-oxy-4-pyridyl, 1,4-dihydro-4-oxo-1-pyridyl,1,4-dihydro-4-oxo-2-pyridyl or 1,4-dihydro-4-oxo-3-pyridyl, optionallyhaving a lower alkyl. Z is preferably vinyl and sulfur. A is preferablyan alkylene having 3 or 4 carbon atoms, J is a R8, R9 and R10 havingphenyl. K is preferably 1,4-dihydro-4-oxo-1-pyridyl, N-oxy-4-pyridyl andpyridyl. Preferable examples of K are shown below. ##STR20## J ispreferably 3,4-dimethoxyphenyl or 3,5-dimethoxyphenyl.

The most preferable compound has the following formula (F). A" is analkylene having 3 to 6 carbon atoms. Excluded from the formula are caseswhere A" is n-C3H6, R6 is hydrogen, R7 is methyl, n is 2 and the R8, R9and R10 having phenyl is 3,4-dimethoxyphenyl. However, preferable is acase where A" is an alkylene having 3 or 4 carbon atoms, n is 2 and thephenyl is 3,5-dimethoxy or 3,4-dimethoxy. ##STR21##

In the formula (I'), it is preferred that R1 is R2R2'N--CX--NH-- and Ais an alkyl having 3 or 4 carbon atoms. For other preferablyembodiments, R1 is ##STR22## and A is an alkyl having 4 carbon atoms. R1is imidazolyl and A is an alkyl having 4 carbon atoms. R1 is imidazolyl,A is an alkyl having 4 carbon atoms and J is 3,4-dimethoxyphenyl or3,5-dimethoxyphenyl. J is 3,4-dimethoxyphenyl or 3,5-dimethoxyphenyl. R1is ##STR23##

The following compounds are preferred. ##STR24##

    ______________________________________                                         1  (E)-N-[3-((N'-(2-(3,4-Dimethoxyphenyl)ethyl)-N'-                              methyl)amino)propyl]-4-(4-(N.sup.3 -methyl-N.sup.2 -cyano-                    guadino)phenyl)-3-butenamide                                               2  (E)-N-[3-((N'-(2-(3,5-Dimethoxyphenyl)ethyl)-N'-                              methyl)amino)propyl]-4-(4-(N.sup.3 -methyl-N.sup.2 -cyanoguadino)-            phenyl)-3-butenamide                                                       3  (E)-N-[4-((N'-(2-(3,5-Dimethoxyphenyl)ethyl)-N'-                              methyl)amino)butyl]-4-(4-(1,4-dihydro-4-oxo-1-                                pyridyl)phenyl)-3-butenamide                                               4  (E)-N-[4-((N'-(2-(3,5-Dimethoxyphenyl)ethyl)-N'-                              methyl)amino)butyl]-4-(4-(1H-imidazol-1-yl)phenyl)-                           3-butenamide                                                               6  (E)-N-[4-((N'-(2-(3,5-Dimethoxyphenyl)ethyl)-N'-                              methyl)amino)butyl]-4-(4-nitro-1H-imidazol-1-yl)-                             phenyl]-3-butenamide                                                       7  (E)-N-[4-((N'-(2-(3,5-Dimethoxyphenyl)ethyl)-N'-                              methyl)amino)butyl]-4-(2-(1H-imidazol-1-yl)thiophen-                          5-yl)-3-butenamide                                                         8  (E)-N-[3-((N'-(2-(3,5-Dimethoxyphenyl)ethyl)-N'-                              methyl)amino)propyl]-4-(4-(1,4-dihydro-4-oxo-1-                               pyridyl)phenyl)-3-butenamide                                               9  (E)-N-[3-((N'-(2-(3,5-Dimethoxyphenyl)ethyl)-N'-                              methyl)amino)propyl]-4-(4-(N.sup.2 -methylthioureido)phenyl)-                 3-butenamide                                                              10  (E)-N-[4-((N'-(2-(3,4-Dimethoxyphenyl)ethyl)-N'-                              methyl)amino)butyl]-4-(4-(1H-imidazol-1-yl)phenyl)-                           3-butenamide                                                              11  (E)-N-[4-((N'-(2-(3,4-Dimethoxyphenyl)ethyl)-N'-                              methyl)amino)butyl]-4-(4-(1,4-dihydro-4-oxo-1-                                pyridyl)phenyl)-3-butenamide                                              12  (E)-N-[4-((N'-(2-(3,4-Dimethoxyphenyl)ethyl)-N'-                              methyl)amino)butyl]-4-(4-(N.sup.3 -methyl-N.sup.2 -cyanoguanidino)-           phenyl)-3-butenamide                                                      13  (E)-N-[4-((N'-(2-(3,5-Dimethoxyphenyl)ethyl)-N'-                              methyl)amino)butyl]-4-(4-(N.sup.3 -methyl-N.sup.2 -cyanoguanidino)-           phenyl)-3-butenamide                                                      16  (E)-N-[3-((N'-(2-(3,4-Dimethoxyphenyl)ethyl)-N'-                              methyl)amino)butyl]-4-(4-(1,4-dihydro-4-oxo-1-                                pyridyl)phenyl)-3-butenamide                                              22  (E)-N-[4-((N'-(2-(4-Methoxyphenyl)ethyl)-N'-methyl)-                          amino)butyl]-4-(4-(1H-imidazol-1-yl)phenyl)-3-butenamide                  23  (E)-N-[4-((N'-(2-(4-Methoxyphenyl)ethyl)-N'-methyl)-                          amino)butyl]-4-(4-(1H-imidazol-1-yl)phenyl)-3-                                butenamide                                                                27  (E)-N-[4-((N'-(2-(4-Methoxy-3-methylphenyl)ethyl)-                            N'-methyl)amino)butyl]-4-(4-(1H-imidazol-1-yl)phenyl)-                        3-butenamide                                                              29  (E)-N-[3-((N'-(2-(3,4-Dimethoxyphenyl)ethyl)-N'-                              methyl)amino)propyl]-4-(4-(N.sup.2 -methylureido)phenyl)3-                30  (E)-N-[4-((N'-(2-(3,5-Dimethoxyphenyl)ethyl)-N'-                              methyl)amino)butyl]-4-(4-(N.sup.2 -methylureido)phenyl)-                      3-butenamide                                                              31  (E)-N-[3-((N'-(2-(3,5-Dimethoxyphenyl)ethyl)-N'-                              methyl)amino)propyl]-4-(4-(N.sup.2 -methylthioureido)phenyl)-                 3-butenamide                                                              32  (E)-N-[4-((N'-(2-(3,4-Dimethoxyphenyl)ethyl)-N'-                              methyl)amino)propyl]-4-(4-((1-methylamino-2-nitroethen-                       1-yl)amino)phenyl]-3-butenamide                                           37  (E)-N-[4-((N'-(2-(4-Methoxyphenyl)ethyl)-N'-methyl)                           amino)butyl]-4-(4-(N.sup.3 -methyl-N.sup.2 -cyanoguanidino)phenyl)-           3-butenamide                                                              38  (E)-N-[4-((N'-(2-(3-Methoxyphenyl)ethyl)-N'-methyl)                           amino)butyl]-4-(4-(N.sup.3 -methyl-N.sup.2 -cyanoguanidino)phenyl)-           3-butenamide                                                              42  (E)-N-[3-((N'-(2-(3,4-Dimethoxyphenyl)ethyl)-N'-                              methyl)amino)propyl]-4-(4-(1,4-dihydro-4-oxopryimidin-                        2-yl)phenyl)-3-butenamide                                                     (E)-N-[4-((N'-(2-(3,5-Dimethoxyphenyl)ethyl)-N'-                              methyl)amino)butyl]-4-(4-(1,4-dihydro-4-oxopyrimidin-                         2-yl)phenyl)-3-butenamide                                                 46  (E)-N-[4-((N'-(2-(3,4-Dimethoxyphenyl)ethyl)-N'-                              methyl)amino)butyl]-4-(2-(1H-imidazol-1-yl)thiophen-                          5-yl)-3-butenamide                                                        47  (E)-N-[4-((N'-(2-(3,4-Dimethoxyphenyl)ethyl)-N'-                              methyl)amino)butyl]-4-(4-(4-pyridyl)phenyl)-3-                                butenamide                                                                48  (E)-N-[4-((N'-(2-(3,4-Dimethoxyphenyl)ethyl)-N'-                              methyl)amino)butyl]-4-(4-(3-pyridyl)phenyl)-3-                                butenamide                                                                49  (E)-N-[4-((N'-(2-(3,5-Dimethoxyphenyl)ethyl)-N'-                              methyl)amino)butyl]-4-(4-(3-pyridyl)phenyl)-3-                                butenamide                                                                50  (E)-N-[4-((N'-(2-(4-Nitrophenyl)ethyl)-N'-methyl)                             amino)butyl]-4-(4-(1H-imidazol-1-yl)phenyl)-3-                                butenamide                                                                51  (E)-N-[4-((N'-(2-(3,4-Dimethoxyphenyl)ethyl)-N'-                              methyl)amino)propyl]-4-(4-((1-methylimidazolin-4-                             on-2-yl)amino)phenyl]-3-butenamide                                        55  (E)-N-[4-(N'-(2-(3,5-Dimethoxyphenyl)ethyl)-N'-methyl)                        amino)butyl]-4-(5-(1,4-dihydro-4-oxo-1-pyridyl)thiophen-2-yl]             3-butenamide                                                                  56  (E)-N-[4-(2-(3,5-Dimethoxyphenyl)ethyl)-N'-methyl)amino)                      butyl]-4-(5-(1H-imidazol-1-yl)furan-2-yl]-3-butenamide                    57  (E)-N-[4-(N'-(2-(3,4-Dimethoxyphenyl)ethyl)-N'-methyl)                        amino)butyl]-4-[4-(N-oxy-4-pyridyl)phenyl]-3-butenamide                   58  (E)-N-[3-((N'-(2-(3,4-Dimethoxyphenyl)ethyl)-N'-methyl)                       amino)butyl]-4-(4-(N.sup.3 -methyl-N.sup.2 -cyanoguanidino)phenyl]-       3-butenamide                                                                  61  (E)-N-[4-(N'-(2-(3,4-Dimethoxyphenyl)ethyl)-N'-methyl)                        amino)butyl]-4-(5-(3-pyridyl)thiophen-2-yl]-3-butenamide                  62  (E)-N-[4-(N'-(2-(3,5-Dimethoxyphenyl)ethyl)-N'-methyl)                        amino)butyl]-4-(5-(3-pyridyl)thiophen-2-yl]-3-butenamide                  65  (E)-N-[4-(N'-(2-(3,4-Dimethoxyphenyl)ethyl)-N'-methyl)                        amino)butyl]-4-(4-(2-methoxy-5-pyridyl)phenyl]-3-                             butenamide                                                                66  (E)-N-[4-(N'-(2-(3,4-Dimethoxyphenyl)ethyl)-N'-methyl)                        amino)butyl]-4-[4-(1,2-dihydro-1-methyl-2-oxo-5-pyridyl)                      phenyl]-3-butenamide                                                      67  (E)-N-[3-(N'-(2-(3,5-Dimethoxyphenyl)ethyl)-N'-methyl)                        amino)propyl]-4-(4-(N.sup.3 -ethyl-N.sup.2 -cyanoguanidino)phenyl]-3-         1                                                                             butenamide                                                                68  (E)-N-[3-(N'-(2-(3,5-Dimethoxyphenyl)ethyl)-N'-methyl)                        amino)propyl]-4-(4-(N.sup.3 -i-propyl-N.sup.2 -cyanoguanidino)phenyl]-        3-                                                                            butenamide                                                                69  (E)-N-[4-(N'-(2-(3,5-Dimethoxyphenyl)ethyl)-N'-methyl)                        amino)butyl]-4-(4-(N.sup.3 -ethyl-N.sup.2 -cyanoguanidino)phenyl]-3-          butenamide                                                                70  (E)-[N-[4-(N'-(2-(3,5-Dimethoxyphenyl)ethyl)-N'-methyl)                       amino)butyl]-4-(4-(N.sup.3 -n-propyl-N.sup.2 -cyanoguanidino)phenyl]      3-butenamide                                                                  71  (E)-[N-[4-(N'-(2-(3,5-Dimethoxyphenyl)ethyl)-N'-methyl)-                      amino)butyl]-4-(4-(N.sup.3 -i-propyl-N.sup.2 -cyanoguanidino)phenyl]      3-butenamide                                                                  ______________________________________                                    

The invention provides a pharmacological composition which comprises apharmacologically effective amount of the compound or salt as definedabove and a pharmacologically acceptable carrier. It also provides amethod for treating, preventing, remitting or ameliorating ischemicheart diseases by administering the compound or salt defined above in apharmacologically effective amount to a human being.

The pharmacologically acceptable salt of the present invention includesinorganic acid salts such as hydrochloride, sulfate, hydrobromide andphosphate and organic acid salts such as formate, acetate, maleate,fumarate, tartrate, methanesulfonate, benzenesulfonate andtoluenesulfonate.

Although optical isomers or tautomers are present depending upon thekind of the substituent of the compound according to the presentinvention, it is a matter of course that they fall within the scope ofthe present invention.

Representative processes for the preparation of the compound accordingto the present invention will now be described.

PREPARATION PROCESS

A butenoic acid derivative represented by the general formula (I)wherein the moiety represented by the formula: ##STR25## is a phenylgroup, i.e., one represented by the following general formula: ##STR26##(wherein R¹, R⁶, R⁷, A, J and n are each as defined above) is preparedaccording to, for example, the following process: ##STR27## (wherein R¹,R⁶, R⁷, A, n and J are each as defined above.)

Namely, the objective compound (I') can be prepared by reacting acarboxylic acid represented by the general formula (II) or a reactivederivative thereof with an amino compound represented by the generalformula (III) to carry out amidation.

The reactive derivative of the compound (II) includes acid halidethereof such as acid chloride thereof and acid bromide thereof; acidazide; active esters thereof with N-hydroxybenzotriazole orN-hydroxysuccinimide; symmetric acid anhydride thereof and mixed acidanhydride thereof with alkylcarbonic acid or p-toluenesulfonic acid.

When the compound (II) to be used is of free acid type, the abovereaction is preferably carried out in the presence of a condensing agentsuch as dicyclohexylcarbodiimide, 1,1'-carbonyldiimidazole, ethylchloroformate, diethyl azodicarboxylate or dipyridyl disulfide at a roomtemperature or under cooling at a temperature of -78° C. or above or byheating under reflux.

The reaction is carried out in water or an organic solvent which isinert to the reaction, for example, methanol, ethanol, pyridine,tetrahydrofuran, dioxane, ether, benzene, toluene, xylene, methylenechloride, dichloroethane, chloroform, dimethylformamide, methylenechloride, ethyl acetate or acetonitrile by using substantially equimolaramounts of a compound (II) or a reactive derivative thereof and acompound (III) or by using a slight excess of either of them.

Depending upon the kind of the reactive derivative, it is sometimes,advantageous for smoothing the progress of the reaction that a base suchas diisopropylethylamine, triethylamine, pyridine, picoline, lutidine,N,N-dimethylaniline, 4-dimethylaminopyridine, potassium carbonate orsodium hydroxide is used in the reaction.

Although the reaction temperature is not particularly limited but variesdepending upon the kind of the reactive derivative, the reaction isgenerally carried out at a temperature of from -20° C. to the refluxtemperature to obtain the objective compound.

The compound represented by the general formula (II) to be used as astarting material according to the present invention can be prepared by,for example, the following process: ##STR28## (In the above series offormulas, R¹ is as defined above and Ph represents a phenyl group)

Step 1

In this step, a compound represented by the general formula (V) isreacted with a compound represented by the general formula (IV) in thepresence of a copper catalyst such as powdered copper or copper oxideaccording to the Ullmann reaction to obtain a compound (VI). Thisreaction may be carried out in the absence of any solvent or in thepresence of an organic solvent which is inert to the reaction, forexample, nitrobenzene, dimethylformamide or pyridine, or water.

Alternatively, a compound represented by the general formula (VI) can bealso prepared by reacting a compound represented by the general formula(V) with a salt of a compound represented by the general formula (IV)with a metal such as lithium, sodium or potassium to carry out thereplacement.

This reaction may be carried-out in the absence of any solvent or in thepresence of an organic solvent which is inert to the reaction, forexample, dimethylformamide, dimethylacetamide, dimethyl sulfoxide,dioxane, ether or tetrahydrofuran.

Step 2

A compound (II) can be prepared by reacting a compound represented bythe general formula (VI) with a compound represented by the generalformula (VI') in a solvent such as ether, tetrahydrofuran, dioxane,dimethylformamide, dimethylacetamide or dimethyl sulfoxide in thepresence of t-butoxypotassium, caustic potash, caustic soda, sodiummethoxide, sodium ethoxide or sodium hydride at a temperature of from-78° C. to a room temperature according to an ordinary process.

Alternatively, the compound represented by the above general formula(II) can be also prepared by, for example, the following process: [whenR¹ is a group represented by the formula: ##STR29## wherein R² is asdefined above, R² is a hydrogen atom and X is a group represented by theformula: ═N--R³ (wherein R³ is as defined above)] ##STR30## (In theabove series of formulas, R² and R³ are each as defined above)

Step 1

In this step, a compound represented by the general formula (VII) isprepared by hydrolyzing the alkanoylamino group of a compoundrepresented by the general formula (II') under an acidic or basiccondition according to a conventional process and esterifying theobtained product according to a conventional process.

This hydrolysis is carried out in a solvent such as water,water-containing methanol, water-containing ethanol, water-containingtetrahydrofuran, or water-containing dioxane in the presence ofhydrochloric acid, sodium hydroxide, potassium hydroxide or lithiumhydroxide at a room temperature or by heating under reflux.

This esterification is carried out in a solvent such as methanol,ethanol or propanol in the presence of hydrogen chloride, concentratedsulfuric acid or p-toluenesulfonic acid at a room temperature or byheating under reflux.

Step 2

In this step, a compound represented by the general formula (VII) isreacted with a compound represented by the general formula (VIII) toobtain a compound represented by the general formula (IX).

This reaction is preferably carried out in the absence of any solvent orin the presence of a solvent inert to the reaction, for example,chloroform, dichloromethane, dichloroethane, tetrahydrofuran, dioxane,benzene, toluene, xylene or dimethylformamide at a room temperature orby heating under reflux.

Step 3

In this step, a compound represented by the general formula (IX) isreacted with a compound represented by the general formula (X) in thepresence of a condensing agent such as N,N'-dicyclohexylcarbodiimide toobtain a compound represented by the general formula (XI).

The reaction is preferably carried out in the absence of any solvent orin the presence of an organic solvent inert to the reaction, forexample, chloroform, dichloromethane, dichloroethane, ether,tetrahydrofuran, dioxane, acetonitrile, benzene, toluene or xylene at aroom temperature or by heating under reflux.

Alternatively, a compound represented by the general formula (XI) can beprepared by reacting a compound represented by the general formula (IX)with dimethyl sulfate, trimethyloxonium tetrafluoroborate,triethyloxonium tetrafluoroborate, methyl iodide or ethyl iodideaccording to a conventional process to obtain an isourea or isothioureaderivative and reacting the isourea or isothiourea derivative with acompound represented by the general formula (X) or a salt thereof withlithium, sodium or potassium.

This reaction is preferably carried out in the absence of any solvent orin the presence of an organic solvent inert to the reaction, forexample, chloroform, dichloromethane, dichloroethane, ether,tetrahydrofuran, dioxane, acetonitrile, benzene, toluene or xylene at aroom temperature or by heating under reflux.

Step 4

A compound represented by the general formula (XI) is hydrolyzed underan acidic or basic condition according to a conventional process toobtain a compound represented by the general formula (II").

This hydrolysis is carried out in a solvent such as water,water-containing methanol, water-containing ethanol, water-containingtetrahydrofuran or water-containing dioxane in the presence ofhydrochloric acid, sodium hydroxide, potassium hydroxide or lithiumhydroxide at a room temperature or by heating under reflux.

When R¹ is a group represented by the formula: ##STR31## wherein R² isas defined above and X is an oxygen or sulfur atom (i.e., when R^(2') isH), as will be described below, a compound represented by the generalformula: ##STR32## can be easily prepared by hydrolyzing a compoundrepresented by the general formula (IX) in a similar manner to thatdescribed in the above Step 4.

Alternatively, a compound represented by the general formula (XI) can beprepared by the following process: ##STR33## (In the above series offormulas, R², R³ and R¹³ are each as defined above)

Namely, a compound represented by the general formula (XI) can beprepared by reacting a compound represented by the general formula (VII)with a compound represented by the general formula (XIII) and reactingthe obtained product with an amine represented by the general formula(XV) or a salt thereof with lithium, sodium or potassium or by reactinga compound represented by the general formula (VII) with a compoundrepresented by the general formula (XII).

These reactions are each preferably carried out in the absence of anysolvent or in the presence of an organic solvent inert to the reaction,for example, chloroform, dichloromethane, dichloroethane, ether,tetrahydrofuran, dioxane, acetonitrile, benzene, toluene or xylene at aroom temperature or by heating under reflux.

Further, the compound represented by the general formula (II) can bealso prepared by the following processes: ##STR34## (In the above seriesof formulas, R⁴, R⁵ and R¹³ are each as defined above)

Step 1

A compound represented by the general formula (XX) can be prepared byreacting a compound represented by the general formula (VII) with anortho ester compound represented by the general formula (XVII) such asmethyl orthoformate, ethyl orthoformate, methyl orthoacetate, ethylorthoacetate, methyl orthopropionate or ethyl orthopropionate andreacting the obtained product with an amine represented by the generalformula (XIX) or a salt thereof with lithium, sodium or potassium or byreacting a compound represented by the general formula (VII) with acompound represented by the general formula (XVI).

These reactions are each preferably carried out in the absence of anysolvent or in the presence of an organic solvent inert to the reaction,for example, chloroform, dichloromethane, dichloroethane, ether,tetrahydrofuran, dioxane, acetonitrile, benzene, toluene or xylene at aroom temperature or by heating under reflux.

Step 2

A compound represented by the general formula (XX) is hydrolyzed underan acidic or basic condition to obtain a compound represented by thegeneral formula (II"")

This hydrolysis is carried out in a solvent such as water,water-containing methanol, water-containing ethanol, water-containingtetrahydrofuran or water-containing dioxane in the presence ofhydrochloric acid, sodium hydroxide, potassium hydroxide or lithiumhydroxide at a room temperature or by heating under reflux.

Further, a compound represented by the general formula (IX) wherein X'is a sulfur atom can be also prepared by the following process:##STR35## (In the above series of formulas, R², R^(2') and R¹³ are eachas defined above)

Step 1

In this step, a compound represented by the general formula (VII) isreacted with thiophosgene in the presence or absence of a base to obtaina compound represented by the general formula (VII'). The base may betriethylamine, pyridine or 2,6-lutidine.

This reaction is preferably carried out in the absence of any solvent orin the presence of an organic solvent inert to the reaction, forexample, chloroform, dichloromethane, dichloroethane, tetrahydrofuran,dioxane, benzene, toluene, xylene or dimethylformamide at ordinarytemperatures or under cooling with ice or by heating under reflux.

Step 2

In this step, a compound represented by the general formula (VII') isreacted-with a compound represented by the general formula (XV') toobtain a compound represented by the general formula (IX').

This reaction is preferably carried out in the absence of any solvent orin the presence of an organic solvent inert to the reaction, forexample, chloroform, dichloromethane, dichloroethane, ether,tetrahydrofuran, dioxane, acetonitrile, benzene, toluene or xylene atordinary temperatures or under cooling with ice or by heating underreflux.

On the other hand, another starting material, i.e., the compound (III)can be prepared by, for example, the following processes: ##STR36## (Inthe above series of formulas, R⁶, R⁷, n, A and J are each as definedabove)

Step 1

In this step, a compound represented by the general formula (XXI) isreacted with a compound represented by the general formula (XXII)according to a conventional process to obtain a compound (XXIII).

More particularly, the reaction between the both is carried out in asolvent such as benzene, toluene, xylene, dimethylformamide,acetonitrile, dimethyl sulfoxide, dioxane or tetrahydrofuran in thepresence of a base such as potassium carbonate, sodium carbonate,triethylamine or diisopropylethylamine under heating to obtain acompound (XXIII).

Step 2

A compound represented by the general formula (XXIII) wherein Y' is aleaving group such as a halogen atom or a methanesulfonyloxy group isconverted into a compound (XXV) by the reaction thereof with an alkalimetal salt of phthalimide (XXIV) such as potassium or sodium saltthereof in the presence of a base such as potassium carbonate or sodiumcarbonate. On the other hand, a compound represented by the generalformula (XXIII) wherein Y' is a protected hydroxyl group such as atrityloxy or tertbutyldimethylsiloxy group is converted into a compound(XXV) by removing the protective group from the compound according to aconventional process and subjecting the obtained product to the reactionwith phthalimide, triphenylphosphine and diethyl azodicarboxylate. Inthis reaction, a solvent which is inert to the reaction is used andexamples thereof include dimethyl sulfoxide, dimethylacetamide,dimethylacetamide, acetonitrile and tetrahydrofuran.

Step 3

A compound (III') (corresponding to the compound represented by theformula (III) wherein R⁶ is H) can be prepared by heating a compoundrepresented by the general formula (XXV) together with, for example,hydrazine monohydrate under reflux in the presence of an organic solventsuch as methanol or ethanol.

Step 4

A compound represented by the general formula (III) can be prepared byreacting a compound represented by the general formula (III')(corresponding to a compound represented by the general formula (III)wherein R⁶ is H) with an aldehyde or ketone in the presence of acatalyst such as palladium/carbon, platinum oxide or Raney nickel in-anatmosphere of hydrogen to carry out reductive amination.

The aldehyde or ketone to be used in this step may be acetone,cyclobutanone, cyclopentanone or benzaldehyde. Further, a solvent suchas methanol, ethanol, benzene, toluene, xylene, dimethylformamide,tetrahydrofuran, dioxane or ethyl acetate may be used in this step.

Alternatively, a compound represented by the general formula (III) canbe prepared by converting a compound represented by the general formula(III') into an acid amide or carbamate, such as N-formyl, N-acetyl,N-methoxycarbonyl or N-ethoxycarbonyl derivative according to aconventional process and reducing the obtained acid amide or carbamatewith a metal hydride complex such as lithium aluminum hydride or borane.

This reduction is carried out in a solvent such as ether,tetrahydrofuran, dioxane, 1,2-dimethoxyethane or diethylene glycoldimethyl ether at a room temperature or by heating under reflux.

Alternatively, the compound (XXV) can be prepared by the followingprocess: ##STR37## (In the above series of formulas, R⁷, n, A and J areeach as defined above)

Namely, a compound (XXV) can be prepared by reacting a compoundrepresented by the general formula (XXI) with a compound (XXVI) in thepresence of a base such as potassium carbonate, sodium carbonate,triethylamine or diisopropylethylamine at a room temperature or byheating under reflux.

In this reaction, a solvent such as dimethyl sulfoxide,dimethylformamide, dimethylacetamide or acetonitrile may be used.##STR38## (In the above series of formulas, R⁷, n and J are each asdefined above)

Step 1

A compound represented by the general formula (XXI) is reacted with acompound represented by the general formula (XXVII) in the absence ofany solvent or in the presence of a solvent such as dichloromethane,chloroform, acetonitrile, dimethylformamide, dimethyl sulfoxide, ether,tetrahydrofuran, methanol or ethanol by heating under reflux to obtain acompound (XXVIII).

Step 2

A compound represented by the general formula (XXVIII) is hydrogenatedin the presence of a catalyst such as palladium/carbon, platinum oxideor Raney nickel to obtain a compound represented by the formula (III").

This hydrogenation is carried out in a solvent such as methanol,ethanol, dimethylformamide or ethyl acetate under a normal or elevatedpressure at an ordinary or higher temperature. ##STR39## (In the aboveseries of formulas, R⁶, R⁷, n and J are each as defined above)

A lactam represented by the general formula (XXIX) is hydrolyzed underan acidic or basic condition according to a conventional process toobtain a compound represented by the general formula (XXX).

This hydrolysis is carried out in a solvent such as water,water-containing methanol, water-containing ethanol, water-containingtetrahydrofuran or water-containing dioxane in the presence ofhydrochloric acid, sodium hydroxide, potassium hydroxide or lithiumhydroxide at a room temperature or by heating under reflux.

Step 2

A compound represented by the general formula (XXXII) can be prepared byreacting a compound represented by the general formula (XXX) with acompound represented by the general formula (XXXI) to carry out theacylation and methylating the obtained product with diazomethane.

This acylation is carried out in an organic solvent such asdichloromethane, choloroform, acetonitrile, dimethylformamide, ether,tetrahydrofuran, dioxane, benzene, toluene or xylene in the presence ofa base such as triethylamine, pyridine, potassium carbonate or sodiumcarbonate at an ordinary temperatures or under cooling with ice or byheating under reflux.

Step 3

A compound represented by the general formula (XXXIV) can be prepared byreacting a compound represented by the general formula (XXXII) with acompound represented by the general formula (XXXIII) to carry outamidation.

This reaction is carried out in the absence of any solvent or in thepresence of an organic solvent inert to the reaction, for example,methanol, ethanol, dichloromethane, chloroform, tetrahydrofuran, ether,dioxane, benzene, toluene, xylene or dimethyl sulfoxide at a roomtemperature or by heating under reflux.

Step 4

A compound represented by the general formula (XXXIV) is reduced with ametal hydride such as lithium aluminum hydride or borane to obtain acompound represented by the general formula (III"'). This reduction iscarried out in an organic solvent such as tetrahydrofuran, ether,dioxane, 1,2-dimethoxyethane or diethylene glycol dimethyl ether at aroom temperature or by heating under reflux.

Objective compounds of the present invention other than thoserepresented by the following general formula: ##STR40## (wherein R¹, R⁶,R⁷, n, A and J are each as defined above), i.e., compounds representedby the general formula (I') wherein the moiety represented by theformula: ##STR41## is replaced by the group represented by the formula:##STR42## wherein Z' represents an oxygen or sulfur atom or anazomethyne group) can be prepared by the same processes as thosedescribed above. ##STR43##

(R⁶ in the formula (III) represent H).

In the above formulae, R⁷, n and J are as defined above.

1st step

A compound (XXXVI) can be obtained by reacting a compound of formula(XXI) with a compound of formula (XXXV) without using any solvent or ina solvent such as dichloromethane, chloroform, acetonitrile,N,N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, 1,4-dioxane,methanol or ethanol at room temperature or by heating under reflux.

2nd step

A compound of formula (III") can be obtained by hydrogenating a compoundof formula (XXXVI) in the presence of a catalyst such aspalladium-carbon, platinum oxide or Raney nickel.

The reaction solvents usable in this step include methanol, ethanol,etc. The reaction is conducted at ambient or elevated temperature underatmospheric or elevated pressure.

Pharmacological Test Examples will now be described in order to describethe effect of the compound according to the present invention in detail.

PHARMACOLOGICAL TEST EXAMPLES Coronary Blood Flow Increasing Effect onAnesthetized Thracotomized Dog

Mongrel dogs were thoracotomized under the inhalation anesthesia ofenflurane. In the measurement of coronary blood flow an electromagneticflow probe was applied to the left circumflex coronary artery of thedog.

The test compounds at a dose of 0.03 mg/kg were administeredintravenously via a catheter inserted into the femoral vein.

The effect of increasing the coronary blood flow was evaluated by theratio of change in the blood flow (based on that before theadministration) and is shown by a symbol (+) according to the criteriawhich will be described.

The results are given in Table 1.

                  TABLE 1                                                         ______________________________________                                        Coronary blood flow increasing effect on                                      anesthetized thoracotomized dog                                               Test compound                                                                              Coronary blood flow (CBF)                                        ______________________________________                                        Compound A   ++                                                               Compound B   ++                                                               Compound C   +++                                                              Compound D   ++++                                                             Compound E   ++                                                               Compound F   +                                                                Compound G   ++++                                                             Compound H   +                                                                Compound I   +                                                                Compound J   +                                                                Compound K   +                                                                Compound L   ++++                                                             Compound M   +++                                                              Compound N   ++                                                               Compound O   ++                                                               Compound P   +                                                                Compound Q   ++                                                               ______________________________________                                         Test compounds K, O, P and Q were administered at a dose of 0.01 mg/kg.       Note) The symbols "+", "++", "+++"and "++++" in the above Table represent     the rates of increase in coronary blood flow given in the Table 2,            respectively.                                                            

                  TABLE 2                                                         ______________________________________                                        Rate of increase in CBF                                                       ______________________________________                                        +             1 ˜ 100%                                                  ++           101 ˜ 200%                                                 +++          201 ˜ 300%                                                 ++++         >300%                                                            ______________________________________                                    

The test compounds A to Q used in the above Test Examples are asfollows:

Compound A (Compound of Example 4)

(E)-[N-(4-((N'-(2-(3,5-Dimethoxyphenyl)ethyl)-N'-methyl)amino)butyl]-4-(4-(1H-imidazol-1-yl)-phenyl)-3-butenamide

Compound B (Compound of Example 3)

(E)-[N-(4-((N'-(2-(3,5-Dimethoxyphenyl)ethyl)-N'-methyl)amino)butyl]-4-(4-(1,4-dihydro-4-oxo-1-pyridyl)phenyl)-3-butenamide

Compound C (Compound of Example 1)

(E)-[N-(3-((N'-(2-(3,4-Dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl]-4-(4-(N³-methyl-N² -cyanoguanidino)phenyl)-3-butenamide

Compound D (Compound of Example 2)

(E)-[N-(3-((N'-(2-(3,5-Dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl]-4-(4-(N³-methyl-N² -cyanoguanidino)phenyl)-3-butenamide

Compound E (Compound of Example 20)

(E)-[N-(4-((N'-(2-(3,4-Dimethoxyphenyl)ethyl)-N'-methyl)amino)pentyl]-4-(4-(1H-imidazol-1-yl)phenyl)-3-butenamide

Compound F (Compound of Example 17)

(E)-[N-(3-((N'-(2-(3,5-Dimethoxyphenyl)ethyl)-N'-methyl)amino)butyl]-4-(4-(1,4-dihydro-4-oxo-1-pyridyl)phenyl)-3-butenamide

Compound G (Compound of Example 6)

(E)-N-[4-((N'-(2-(3,5-Dimethoxyphenyl)ethyl)-N'-methyl)amino)butyl]-4-(4-(4-nitro-1H-imidazol-1-yl)phenyl)-3-butenamide

Compound H (Compound of Example 7)

(E)-N-[4-((N'-(2-(3,5-Dimethoxyphenyl)ethyl)-N'-methyl)amino)butyl]-4-(2-(1H-imidazol-1-yl)thiophen-5-yl)-3-butenamide

Compound I (Example 55)

(E)-N-[4-(N'-(2-(3,5-Dimethoxyphenyl)ethyl)-N'-methyl)amino)butyl]-4-(5-(1,4-dihydro-4-oxo-1-pyridyl)thiophen-2-yl]-3-butenamide

Compound J (Example 61)

(E)-N-[4-(N'-(2-(3,4-Dimethoxyphenyl)ethyl)-N'-methyl)amino)butyl]-4-(5-(3-pyridyl)thiophen-2-yl]-3-butenamide

Compound K (Example 57)

(E)-N-[4-(N'-(2-(3,4-Dimethoxyphenyl)ethyl)-N'-methyl)amino)butyl]-4-[4-(N-oxy-4-pyridyl)phenyl]-3-butenamide

Compound L (Example 58)

(E)-N-[3-(N'-(2-(3,4-Dimethoxyphenyl)ethyl)-N'-methyl)amino)butyl]-4-(4-(N.sup.3-methyl-N² -cyanoguanidino)phenyl]-3-butenamide

Compound M (Example 67)

(E)-N-[3-(N'-(2-(3,5-Dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl]-4-(4-(N³-ethyl-N² -cyanoguanidino)phenyl]-3-butenamide

Compound N (Example 68)

(E)-N-[3-(N'-(2-(3,5-Dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl]-4-(4-(N³-i-propyl-N² -cyanoguanidino)phenyl]-3-butenamide

Compound O (Example 69)

(E)-N-[4-(N'-(2-(3,5-Dimethoxyphenyl)ethyl)-N'-methyl)amino)butyl]-4-(4-(N.sup.3-ethyl-N² -cyanoguanidino)phenyl]-3-butenamide

Compound P (Example 70)

(E)-N-[4-(N'-(2-(3,5-Dimethoxyphenyl)ethyl)-N'-methyl)amino)butyl]-4-(4-(N.sup.3-n-propyl-N² -cyanoguanidino)phenyl]-3-butenamide

Compound Q (Example 71)

(E)-N-[4-(N'-(2-(3,5-Dimethoxyphenyl)ethyl)-N'-methyl)amino)butyl]-4-(4-(N.sup.3-i-propyl-N² -cyanoguanidino)phenyl]-3-butenamide

It can be understood from the results of the above describedPharmacological Test Examples that the compounds of the presentinvention each exhibit an excellent coronary vasodilating effect.

Accordingly, the compound of the present invention is effective in thetherapy, prophylaxis, remission and amelioration of ischemic heartdiseases such as coronary arteriosclerosis, various angina pectorisesand myocardial infraction.

When the compound of the present invention is to be used as a drug, itis administered orally or parenterally. Although the dose of thecompound is not particularly limited but varies depending upon thedegree of symptom, the age, sexuality, weight or sensitivity of apatient, the method, timing or interval of administration, theproperties, prescription or kind of pharmaceutical preparation or thekind of an active ingredient, it is about 1 to 1000 mg, preferably about5 to 500 mg, still preferably about 20 to 100 mg, per adult a day, whichmay be administered generally at once or in 2 to 4 portions.

A solid medicine for oral administration containing the compound of thepresent invention as a principal agent is prepared by adding a fillerand, if necessary, a binder, disintegrator, lubricant, coloring agent orcorrigent to the compound and shaping the mixture into a tablet, coatedtablet, granule, powder or capsule.

Examples of the filler include lactose, corn starch, sucrose, glucose,sorbitol, crystalline cellulose and silicon dioxide and those of thebinder include polyvinyl alcohol, polyvinyl ether, ethylcellulose,methylcellulose, acacia, tragacanth, gelatin, shellac,hydroxypropylcellulose, hydroxypropylmethylcellulose, calcium citrate,dextrin and pectin. Examples of the lubricant include magnesiumstearate, talc, polyethylene glycol, silica and hardened vegetable oils.The coloring agent may be any one which is permitted for use in drugs.Examples of the corrigent include powdered cocoa, mentha herb, aromaticpowder, mentha oil, borneol and powdered cinnamon bark. Of course, thetablet or granule may be suitably coated with sugar, gelatin or thelike.

An injection containing the compound of the present invention as aprincipal agent is prepared by, if necessary, mixing the compound with apH regulator, buffer agent, suspending agent, solubilizing agent,stabilizer, tonicity agent and/or preservative and converting themixture into an intravenous, subcutaneous or intramuscular injectionaccording to a conventional method. If necessary, the injection may befreeze-dried by a conventional process.

Examples of the suspending agent include methylcellulose, polysorbate80, hydroxyethylcellulose, acacia, powdered tragacanth,carboxymethylcellulose sodium and polyoxyethylene sorbitan monolaurate.

Examples of the solubilizing agent include polyoxyethylene hardenedcastor oil, polysorbate 80, nicotinamide, polyoxyethylene sorbitanmonolaurate, macrogol and ethyl ester of castor oil fatty acid.

Further, the stabilizer includes sodium sulfite, sodium metasulfite andether, while the preservative includes methyl p-hydroxybenzoate, ethylp-hydroxybenzoate, sorbic acid, phenol, cresol and chlorocresol.

EXAMPLE

Examples of the present invention will now be described, though it is amatter of course that the present invention is not limited to them.

Prior to the description of the examples, processes for the preparationof the starting compounds (raw materials) to be used in the preparationof the compound according to the present invention will first bedescribed.

PREPARATIVE EXAMPLE 1 4-(1,4-Dihydro-4-oxo-1-pyridyl)benzaldehyde##STR44##

30 g of 4-hydroxypyridine was suspended in 500 ml ofN,N-dimethylformamide in a nitrogen atmosphere. The obtained suspensionwas stirred at a room temperature. 13.25 g of sodium hydride (60% inoil) was added to the suspension in portions to form a sodium salt.After one hour, 36.6 ml of 4-fluorobenzaldehyde was added to the mixtureto carry out a reaction at 120° C. for 4 hours. The reaction mixture wascooled by allowing to stand and distilled under a reduced pressure toremove the N,N-dimethylformamide. Ice-water was added to the obtainedresidue. The insoluble matter thus formed was recovered by filtrationand washed with water, acetone and ether successively to obtain 39.04 gof the title compound as a pale yellow powder (yield: 62%).

melting point (° C.): 228 to 230.

    ______________________________________                                        elemental analysis as C.sub.12 H.sub.9 NO.sub.2 :                                        C          H      N                                                ______________________________________                                        calculated (%)                                                                             72.35        4.55   7.03                                         found (%)    72.58        4.64   7.04                                         ______________________________________                                    

NMR (DMSO-d₆) δ; 6.1˜6.4 (2H, m), 7.6˜7.9 (2H, m), 7.9˜8.2 (4H, m),10.05 (1H, s).

PREPARATIVE EXAMPLE 2(E)-4-(4-(1,4-Dihydro-4-oxo-1-pyridyl)phenyl)-3-butenoic acid ##STR45##

4.0 g of 4-(1,4-dihydro-4-oxo-1-pyridyl)benzaldehyde and 8.2 g ofβ-carboxyethyltriphenylphosphonium chloride were suspended in 40 ml oftetrahydrofuran in a nitrogen atmosphere. The obtained suspension wascooled to -5° C., followed by the gradual addition of a solution of 4.96g of potassium tertbutoxide in 30 ml of tetrahydrofuran. The temperatureof the mixture was gradually raised to a room temperature. The resultingmixture was stirred for 14 hours, followed by the addition of ice-water.The obtained aqueous phase was washed with chloroform. The pH of theaqueous phase was adjusted with concentrated hydrochloric acid to about3 to precipitate a crystal. This crystal was recovered by filtration andwashed with water and methanol successively to obtain 3.48 g of thetitle compound as a pale yellow powder (yield: 68%).

melting point (° C.): 275 (dec.).

    ______________________________________                                        elemental analysis as C.sub.15 H.sub.13 NO.sub.3 :                                       C          H      N                                                ______________________________________                                        calculated (%)                                                                             70.58        5.13   5.49                                         found (%)    70.55        5.25   5.46                                         ______________________________________                                    

NMR (DMSO-d₆) δ; 3.21 (2H, d, J=5.6 Hz), 6.1˜6.3 (2H, m), 6.36 (1H, dt,J=5.6 Hz, 16.3 Hz), 6.60 (1H, d, J=16.3 Hz), 7.3˜7.7 (4H, m), 7.8˜8.1(2H, m).

PREPARATIVE EXAMPLE 3 Methyl (E)-4-(4-aminophenyl)-3-butenoate ##STR46##

7.5 g of (E)-4-(4-(acetylamino)phenyl)-3-butenoic acid was dissolved ina 1N aqueous solution of potassium hydroxide. The obtained solution washeated under reflux for 4 hours and cooled by allowing to stand. Afterthe pH of the solution had been adjusted to about 3 by the addition ofconcentrated hydrochloric acid, the resulting solution was concentratedunder a reduced pressure, followed by the addition of benzene. Theobtained mixture was concentrated and freed from the water by azeotropicdistillation to obtain a solid. 300 ml of methanol and 1 ml ofconcentrated sulfuric acid were added to the solid. The obtained mixturewas heated under reflux for 3 hours, cooled by allowing to stand andconcentrated under a reduced pressure. An aqueous solution of potassiumcarbonate was added to the residue and the obtained mixture wasextracted with ethyl acetate. The extract was washed with water and asaturated aqueous solution of common salt successively and dried overanhydrous sodium sulfate. The solvent was distilled off and the residuewas purified by silica gel column chromatography [solvent:n-hexane/ethyl acetate (2:1)] to obtain 5.38 g of the title compound asa lightly orange-colored oil (yield: 82%).

NMR (CDCl₃) δ: 3.20 (2H, d, J=6.2 Hz), 3.6 (2H, br), 3.70 (3H, s), 6.00(1H, dt, J=6.2 Hz, 15.8 Hz), 6.44 (1H, d, J=15.8 Hz), 6.5˜6.7 (2H, m),7.0˜7.2 (2H, m).

PREPARATIVE EXAMPLE 4 Methyl (E)-4-(4-(N²-methylthioureido)phenyl)-3-butenoate ##STR47##

6.00 g of methyl (E)-4-(4-aminophenyl)-3-butenoate was dissolved in 60ml of dioxane, followed by the addition of 2.75 g of methylisothiocyanate. The obtained mixture was kept at 100° C. for 5 hours tocarry out a reaction. After the removal of the solvent from the reactionmixture, ethyl acetate was added to the residue to carry outcrystallization. The insoluble matter thus formed was recovered byfiltration to obtain 4.28 g of the title compound as a pale yellowpowder. Further, the filtrate was concentrated and purified by silicagel column chromatography [solvent: n-hexane/ethyl acetate (1:1)] toobtain 0.95 g of the title compound (total: 5.23 g) (yield: 63%).

melting point (° C.): 129.5 to 130.5.

    ______________________________________                                        elemental analysis as C.sub.13 H.sub.16 N.sub.2 O.sub.2 S:                               C    H          N      S                                           ______________________________________                                        calculated (%)                                                                             59.06  6.10       10.60                                                                              12.13                                     found (%)    59.26  6.15       10.54                                                                              11.99                                     ______________________________________                                    

NMR (CDCl₃) δ; 3.16 (3H, d, J=4.7 Hz), 3.26 (2H, d, J=5.8 Hz), 3.72 (3H,s), 6.10 (1H, br), 6.24 (1H, dt, J=5.8 Hz, 16.2 Hz), 6.51 (1H, d, J=16.2Hz), 7.1˜7.3 (2H, m), 7.3˜7.5 (2H, m), 8.16 (1H, br s).

PREPARATIVE EXAMPLE 5 Methyl (E)-4-(4-(N³ -methyl-N²-cyanoguanidino)phenyl)-3-butenoate ##STR48##

1.90 g of methyl (E)-4-(4-(N² -methylthioureido)phenyl)-3-butenoate wasdissolved in 60 ml of dioxane, followed by the addition of 0.45 g ofcyanamide, 2.23 g of N,N'-dicyclohexylcarbodiimde andN,N-diisopropylethylamine (in a catalytic amount). The obtained mixturewas kept at 100° C. for 3 hours to carry out a reaction. The reactionmixture was cooled by allowing to stand, followed by the addition ofethyl acetate. The mixture was filtered to remove insoluble matter. Theobtained filtrate was concentrated, followed by the addition ofchloroform. The insoluble matter thus formed was recovered by filtrationto obtain the title compound. Further, the filtrate was concentrated andpurified by silica gel column chromatography [solvent:chloroform/methanol (50:1)] to obtain 1.56 g of the title compound as awhite powder (yield: 80%).

melting point (° C.): 190.0 to 192.0.

    ______________________________________                                        elemental analysis as C.sub.14 H.sub.16 N.sub.4 O.sub.2 :                                C          H      N                                                ______________________________________                                        calculated (%)                                                                             61.75        5.92   20.58                                        found (%)    61.89        6.06   20.49                                        ______________________________________                                    

NMR (DMSO-d₆) δ; 2.77 (3H, d, J=4.3 Hz), 3.26 (2H, d, J=7.2 Hz), 3.61(3H, s), 6.25 (1H, dt, J=7.2 Hz, 15.1 Hz), 6.48 (1H, d, J=15.1 Hz),7.0˜7.4 (5H, m), 8.80 (1H, br s).

PREPARATIVE EXAMPLE 6 (E)-4-(4-(N³ -Methyl-N²-cyanoguanidino)phenyl)-3-butenoic acid ##STR49##

1.56 g of methyl (E)-4-(4-(N³ -methyl-N²-cyanoguanidino)phenyl)-3-butenoate was dissolved in 15 ml of dioxane,followed by the addition of 6.9 ml of a 1N aqueous solution of sodiumhydroxide. The mixture was reacted at a room temperature for 8 hours.The reaction mixture was concentrated, followed by the addition ofwater. The obtained aqueous phase was washed with chloroform. The pH ofthe resulting aqueous phase was adjusted to about 3 by the addition ofconcentrated hydrochloric acid to precipitate a crystal. This crystalwas recovered by filtration and washed with water to obtain 0.84 g ofthe title compound as a pale yellow powder (yield: 57%).

melting point (° C.): 176 (dec.)

    ______________________________________                                        elemental analysis as C.sub.13 H.sub.14 N.sub.4 O.sub.2 :                                C          H      N                                                ______________________________________                                        calculated (%)                                                                             60.45        5.46   21.69                                        found (%)    60.51        5.56   21.67                                        ______________________________________                                    

NMR (DMSO-d₆) δ; 2.76 (3H, d, J=5.0 Hz), 3.16 (2H, d, J=5.8 Hz), 6.16(1H, dt, J=5.8 Hz, 15.8 Hz), 6.43 (1H, d, J=15.8 Hz), 6.8˜7.4 (5H, m),8.80 (1H, br s).

PREPARATIVE EXAMPLE 7 Methyl (E)-4-(4-(N²-cyanopropanamidino)phenyl)-3-butenoate ##STR50##

3.38 g of methyl (E)-4-(4-aminophenyl)-3-butenoate and 4.67 g of ethylorthopropionate were mixed together and kept at 150° to 160° C. for onehour to carry out a reaction. The reaction mixture was cooled byallowing to stand and concentrated under a reduced pressure to obtain alightly orange-colored oil. 1.49 g of cyanamide was added to the oil tocarry out a reaction at 150° to 160° C. for 15 minutes. The reactionmixture was cooled by allowing to stand and purified by silica gelcolumn chromatography [solvent: dichloromethane/methanol (100:1)] toobtain 3.39 g of the title compound as a lightly orange-colored solid(yield: 71%).

melting point (° C.): 110 to 120 .

    ______________________________________                                        elemental analysis as C.sub.15 H.sub.17 N.sub.3 O.sub.2 :                                C          H      N                                                ______________________________________                                        calculated (%)                                                                             66.40        6.32   15.49                                        found (%)    66.72        6.34   15.56                                        ______________________________________                                    

NMR (CDCl₃) δ; 1.43 (3H, t, J=7.5 Hz), 2.80 (2H, q, J=7.5 Hz), 3.28 (2H,d, J=5.7 Hz), 3.74 (3H, s), 6.23 (1H, dt, J=5.7 Hz, 15.8 Hz), 6.50 (1H,d, J=15.8 Hz), 7.1˜7.4 (2H, m), 7.4˜7.7 (2H, m), 8.82 (1H, br s).

PREPARATIVE EXAMPLE 8 (E)-4-(4-(N²-Cyanopropanamidino)phenyl)-3-butenoic acid ##STR51##

The same procedure as that of Preparative Example 6 was repeated exceptthat methyl (E)-4-(4-(N² -cyanopropanamidino)phenyl)-3-butenoate wasused to obtain the title compound as a pale yellow powder (yield: 61%).

melting point (° C.): 176 to 178.

    ______________________________________                                        elemental analysis as C.sub.14 H.sub.15 N.sub.3 O.sub.2 :                                C          H      N                                                ______________________________________                                        calculated (%)                                                                             65.35        5.88   16.33                                        found (%)    65.63        5.87   16.56                                        ______________________________________                                    

NMR (DMSO-d₆) δ; 1.31 (3H, t, J=7.9Hz), 2.67 (2H, q, J=7.9 Hz), 3.18(2H, d, J=5.7 Hz), 6.23 (1H, dt, J=5.7 Hz, 15.8 Hz), 6.49 (1H, d, J=15.8Hz), 7.2˜7.6 (4H, m), 10.51 (1H, s), 12.29 (1H, br s).

PREPARATIVE EXAMPLE 9 (E)-4-(4-(N² -Methylthioureido)phenyl)-3-butenoicacid ##STR52##

The same procedure as that of Example 6 was repeated except that methyl(E)-4-(4-(N² -methylthioureido)phenyl)-3-butenoate was used. The titlecompound was obtained as a pale yellow powder (yield: 54%).

melting point (° C.): 150 to 152.

    ______________________________________                                        elemental analysis as C.sub.12 H.sub.14 N.sub.2 O.sub.2 S:                               C    H          N      S                                           ______________________________________                                        calculated (%)                                                                             57.78  5.64       11.19                                                                              12.81                                     found (%)    57.74  5.63       11.02                                                                              12.55                                     ______________________________________                                    

NMR (DMSO-d₆) δ; 2.91 (3H, d, J=4.4 Hz), 3.16 (2H, d, J=6.2 Hz), 6.19(1H, dt, J=6.2 Hz, 15.8 Hz), 6.41 (1H, d, J=15.8 Hz), 7.34 (4H, s), 7.67(1H, br d, J≃4 Hz), 9.49 (1H, br s).

PREPARATIVE EXAMPLE 10 Methyl (E)-4-(4-(N²-methylureido)phenyl-3-butenoate ##STR53##

3.00 g of methyl (E)-4-(4-aminophenyl)-3-butenoate was dissolved in 30ml of 1,4-dioxane, followed by the addition of 1.11 ml of methylisocyanate. The obtained mixture was heated under reflux for 3 hours anddistilled under a reduced pressure to remove the solvent. Ether wasadded to the residue. The insoluble matter thus formed was recovered byfiltration to obtain 0.87 g of the title compound as a pale yellowpowder.

The filtrate was concentrated and purified by silica gel columnchromatography [solvent: dichloromethane/methanol (40:1)] to obtain 0.98g of the title compound as a yellow solid (total: 1.85 g, yield: 48%).

melting point ° C.): 146 to 148.

    ______________________________________                                        elemental analysis as C.sub.13 H.sub.16 N.sub.2 O.sub.3 :                                C          H      N                                                ______________________________________                                        calculated (%)                                                                             62.89        6.50   11.28                                        found (%)    62.89        6.44   11.37                                        ______________________________________                                    

NMR (CDCl₃) δ; 2.73 (3H, d, J=4.8 Hz), 3.22 (2H, d, J=6.2 Hz), 3.70 (3H,s), 5.25˜5.54 (1H, m), 6.12 (1H, dt, J=6.2 Hz, 15.8 Hz), 6.42 (1H, d,J=15.8 Hz), 6.86˜7.39 (5H, m).

PREPARATIVE EXAMPLE 11 (E)-4-(4-(N² -Methylureido)phenyl-3-butenoic acid##STR54##

The same procedure as that of Preparative Example 6 was repeated exceptthat methyl (E)-4-(4-(N-² -methylureido)phenyl)-3-butenoate was used.The title compound was obtained as a lightly orange-colored powder(yield: 74%).

melting point (° C.): 188.5 to 200.5

    ______________________________________                                        elemental analysis as C.sub.12 H.sub.14 N.sub.2 O.sub.3 :                                C          H      N                                                ______________________________________                                        calculated (%)                                                                             61.52        6.02   11.96                                        found (%)    61.60        6.06   11.81                                        ______________________________________                                    

NMR (DMSO-d₆) δ; 2.63 (3H, d, J=4.4 Hz), 3.14 (2H, d, J=7.2 Hz),5.95˜6.05 (1H, m), 6.12 (1H, dt, J=7.2 Hz), 16.0 Hz), 6.38 (1H, d,J=10.0 Hz), 7.25 (2H, d, J=8.8 Hz), 7.35 (2H, d, J=8.8 Hz), 8.52 (1H,s).

PREPARATIVE EXAMPLE 12 Methyl(E)-4-{4-((1-methylthio-2-nitroethen-1-yl)amino)phenyl}-3-butenoate##STR55##

7.00 g of methyl (E)-4-(4-aminophenyl)-3-butenoate was dissolved in 120ml of n-propanol, followed by the addition of 30.28 g of1,1-bis-(methylthio)-2-nitroethylene. The obtained mixture was heatedunder reflux for 3 hours and distilled to remove the solvent. Theresidue was purified by silica gel column chromatography (solvent:dichloromethane). The obtained solid was washed with ethyl ether toobtain 9.65 g of the title compound as a yellow powder (yield: 86%).

melting point (° C.): 136 to 138.5 .

    ______________________________________                                        elemental analysis as C.sub.14 H.sub.16 N.sub.2 O.sub.4 S:                               C    H          N      S                                           ______________________________________                                        calculated (%)                                                                             54.53  5.23       9.09 10.40                                     found (%)    54.51  5.24       8.66 10.22                                     ______________________________________                                    

NMR (CDCl₃) δ; 2.38 (3H, s), 3.27 (2H, d, J=5.7 Hz), 3.72 (3H, s), 6.29(1H, dt, J=5.7 Hz, 15.8 Hz), 6.53 (1H, d, J=15.8 Hz), 6.68 (1H, s), 7.22(2H, d like, J=8 Hz), 7.41 (2H, d like, J=8 Hz), 11.79 (1H, s).

PREPARATIVE EXAMPLE 13 Methyl(E)-4-{4-((1-methylamino-2-nitroethen-1-yl)amino)phenyl}-3-butenoate##STR56##

1.00 g of methyl(E)-4-{4-((1-methylthio-2-nitroethen-1-yl)amino)phenyl}-3-butenoate wassuspended in 5 ml of methanol, followed by the addition of 1.25 ml of a40% solution of methylamine in methanol. The obtained mixture wasstirred at a room temperature for 4 hours and distilled to remove thesolvent. The residue was purified by silica gel column chromatography[solvent: dichloromethane/methanol (30:1)] to obtain 0.5 g of the titlecompound as a pale yellow solid (yield: 54%).

NMR (CDCl₃) δ; 2.91 (3H, br), 3.23 (2H, d, J=5.8 Hz), 3.68 (3H, s), 6.19(1H, dt, J=5.8 Hz, 16.2 Hz), 6.43 (1H, d, J=16.2 Hz), 6.45 (1H, br s),6.96˜7.20 (3H, m), 7.32 (2H, d, J=7.9 Hz), 11.50 (1H, br).

PREPARATIVE EXAMPLE 14(E)-4-{4-((1-Methylamino-2-nitroethen-1-yl)amino)phenyl}-3-butenoic acid##STR57##

The same procedure as that of Preparative Example 6 was repeated exceptthat methyl(E)-4-{4-((1-methylamino-2-nitroethen-1-yl)amino)phenyl}-3-butenoate wasused. The title compound was obtained as a lightly orange-colored powder(yield: 63%).

NMR (DMSO-d₆) δ; 2.94 (3H, d, J=4.3 Hz), 3.16 (2H, d, J=5.4 Hz), 6.12(1H, br s), 6.24 (1H, dt, J=5.4 Hz, 15.5 Hz), 6.48 (1H, d, J=15.5 Hz),7.12 (2H, d, J=7.9 Hz), 7.41 (2H, d, J=7.9 Hz).

PREPARATIVE EXAMPLE 15 Methyl(E)-4-{4-((1,4-dihydro-4-oxopyrimidin-2-yl)amino)pheny}-3-butenoate##STR58##

A mixture comprising 3.00 g of methyl (E)-4-(4-aminophenyl)-3-butenoateand 2.34 g of 2-methylthio-1,4-dihydro-4-oxopyrimidine was stirred at150° to 160° C. for 20 minutes. The reaction mixture was purified bysilica gel column chromatography [solvent: dichloromethane/methanol(30:1)] to obtain 1.58 g of the title compound as a light brown powder(yield: 35%).

NMR (CDCl₃) δ; 3.12 (2H, d, J=5.4 Hz), 3.65 (3H, s), 5.76 (1H, d, J=7.2Hz), 6.05 (1H, dt, J=5.4 Hz, 15.5 Hz), 6.31 (1H, d, J=15.5 Hz),7.08˜7.80 (7H, m). cl PREPARATIVE EXAMPLE 16

(E)-4-{4-((1,4-Dihydro-4-oxopyrimidin-2-yl)amino)phenyl}-3-butenoic acid##STR59##

The same procedure as that of Preparative Example 6 was repeated exceptthat methyl(E)-4-{4-((1,4-dihydro-4-oxopyrimidin-2-yl)amino)phenyl}-3-butenoate wasused. The title compound was obtained as a lightly orange-colored powder(yield: 58%).

NMR (DMSO-d₆) δ; 3.15 (2H, d, J=6.8 Hz), 5.81 (1H, br s), 6.19 (1H, dt,J=6.8 Hz, 15.6 Hz), 6.42 (1H, d, J=15.6 Hz), 7.34 (2H, d, J=8.8 Hz),7.56 (2H, d, J=8.8 Hz), 7.76 (1H, br s).

PREPARATIVE EXAMPLE 17 Methyl(E)-4-{4-((pyrimidin-2-yl)amino)phenyl}-3-butenoate ##STR60##

1.5 g of methyl 4-aminobutenoate, 900 mg of 2-chloropyrimidine and 1.0 gof diisopropylethylamine were dissolved in 20 ml ofN,N-dimethylformamide to obtain a solution. This solution was heatedunder reflux for 6 hours, cooled and distilled under a reduced pressureto remove low-boiling matter. The residue was purified by silica gelcolumn chromatography [solvent: ethyl acetate/hexane (1:30)] to obtain300 mg of the title compound as a white crystal (yield: 14%).

NMR (CDCl₃) δ; 3.23 (2H, d, J=7.2 Hz), 3.70 (3H, s), 6.19 (1H, dt,J=16.0 Hz, 4.8 Hz), 6.44 (1H, d, J=16 Hz), 6.69 (1H, t, J=4.8 Hz), 7.33(2H, d, J=6.8 Hz), 7.57 (2H, d, J=6.8 Hz), 8.05 (1H, s), 8.40 (2H, d,J=4.8 Hz).

PREPARATIVE EXAMPLE 18(E)-4-{4-((Pyrimidin-2-yl)amino)phenyl}-3-butenoic acid ##STR61##

300 mg of methyl (E)-4-{4-((pyrimidin-2yl)amino)phenyl}-3-butenoate wasdissolved in 5 ml of dioxane, followed by the addition of 3 ml of a 1Nsolution of sodium hydroxide. The obtained mixture was stirred at a roomtemperature for 2 hours, followed by the addition of 3 ml of 1Nhydrochloric acid. The crystal thus formed was recovered by filtrationand dried under a reduced pressure to obtain 200 mg of the titlecompound as a white crystal (yield: 70%).

NMR (DMSO-d₆) δ; 3.13 (2H, d, J=8 Hz), 6.16 (1H, dt, J=15 Hz, 8 Hz),6.39 (1H, d, J=15 Hz), 6.82 (1H, t, J=6 Hz), 7.32 (2H, dd, J=8 Hz, 2Hz), 7.72 (2H, dd, J=8 Hz, 2 Hz), 8.47 (2H, d, J=6 Hz), 9.65 (1H, s).

PREPARATIVE EXAMPLE 19 4-(4-Nitro-1H-imidazol-1-yl)benzaldehyde##STR62##

A suspension of 18.6 g of 4-fluorobenzaldehyde and 18.6 g of4-nitroimidazole in 70 ml of dimethylformamide was dropwise added to asuspension of 6.6 g of sodium hydride (60% suspension in mineral oil) in150 ml of dimethylformamide at a room temperature under stirring. Theobtained mixture was stirred at 90° C. for about 5 hours, cooled andpoured into ice-water to precipitate a solid. This solid was recoveredby filtration, washed with water and heated together with ethanol. Themixture was cooled and filtered. The obtained solid was washed withethanol to obtain 18 g of the title compound as a white powder (yield:55%).

melting point (° C.): 235 to 236.

    ______________________________________                                        elemental analysis as C.sub.10 H.sub.7 N.sub.3 O.sub.3 :                                 C          H      N                                                ______________________________________                                        calculated (%)                                                                             55.30        3.25   19.35                                        found (%)    55.39        3.38   19.51                                        ______________________________________                                    

NMR (DMSO-d₆) δ;

7.96˜8.10 (4H, m), 8.68 (1H, s), 9.06 (1H, s), 10.0 (1H, s).

PREPARATIVE EXAMPLE 20(E)-4-((4-Nitro-1H-imidazol-1-yl)phenyl)-3-butenoic acid ##STR63##

10.9 g of 4-(4-nitro-1H-imidazol-1-yl)benzaldehyde and 20.4 g ofβ-carboxyethyltriphenylphosphonium chloride were suspended in 200 ml oftetrahydrofuran, followed by cooling to -70° C. 70 ml of a solution of12.3 g of potassium tert-butoxide in tetrahydrofuran was slowly dropwiseadded to the above suspension under stirring. After the completion ofthe addition, the temperature of the obtained mixture was graduallyraised to a room temperature. The resulting mixture was poured intowater. The obtained mixture was extracted with ethyl acetate. The pH ofthe obtained aqueous phase was adjusted to about 4 to precipitate asolid. This solid was recovered by filtration and washed with water andethanol successively, followed by the addition of 300 ml of ethanol and2 ml of concentrated sulfuric acid. The obtained mixture was refluxedfor about 5 hours and distilled under a reduced pressure to remove theethanol. Water was added to the obtained residue. The obtained mixturewas made alkaline with a dilute aqueous solution of sodium hydroxide andextracted with ethyl acetate. The ethyl acetate phase was washed withwater, dried over magnesium sulfate and purified by silica gel columnchromatography (solvent: hexane/ethyl acetate) to obtain 2.75 g of ethylester of the title compound.

NMR (CDCl₃) δ; 1.28 (3H, t, J=8 Hz), 3.26 (2H, d, J=6 Hz), 4.2 (2H, q,J=8 Hz), 5.8˜6.7 (2H, m), 7.3˜7.5 (4H, m), 7.74 (1H, d, J=1 Hz), 8.04(1H, d, J=1 Hz).

2.7 g of the above ester was dissolved in 50 ml of methanol, followed bythe addition of 14 ml of 1N sodium hydroxide. The obtained mixture wasstirred at 30° to 40° C. for about 2 hours and distilled under a reducedpressure to remove the methanol. The residue was neutralized with 1Nhydrochloric acid to precipitate a solid. This solid was recovered byfiltration and washed with water and ethanol successively to obtain 2.1g of the title compound as a light brown powder.

PREPARATIVE EXAMPLE 21N-Methyl-N-(2-(3,5-dimethoxyphenyl)ethyl)-1,4-diaminobutane ##STR64##

10.0 g of N-methyl-(2-(3,5-dimethoxyphenyl)ethyl)amine was dissolved in130 ml of N,N-dimethylformamide, followed by the addition of 10.63 g ofanhydrous potassium carbonate and 6.12 ml of 4-bromobutyronitrile. Thereaction was carried out at a room temperature for 12 hours. Water wasadded to the reaction mixture. The obtained mixture was extracted withethyl acetate. The ethyl acetate phase was washed with water and asaturated aqueous solution of common salt successively, dried overanhydrous potassium carbonate and distilled to remove the solvent. 150ml of ethanol, 11 ml of concentrated hydrochloric acid and 1 g ofplatinum- oxide were added to the obtained residue to carry outhydrogenation at a room temperature under 3 kg/cm² for 12 hours. Thecatalyst was filtered out and the filtrate was concentrated under areduced pressure, followed by the addition of concentrated aqueousammonia. The obtained mixture was extracted with chloroform. Thechloroform phase was dried over anhydrous potassium carbonate. After thesolvent had been distilled off, the residue was distilled under areduced pressure to obtain 10.85 g of the title compound as a colorlessoil (yield: 80%).

boiling point (° C.): 165˜168 (0.5˜0.9 mmHg)

NMR (CDCl₃) δ;

1.3˜1.9 (6H, m), 2.2˜2.8 (11H, m), 3.75 (6H, s), 6.2˜6.4 (3H, m).

PREPARATIVE EXAMPLE 22

The following compounds were prepared in a similar manner to that ofPreparative Example 21.

N-Methyl-N-(2-phenylethyl)-1,4-diaminobutane ##STR65##

colorless oil.

boiling point (° C.): 108˜114 (˜1 mmHg).

NMR (CDCl₃) δ; 1.15 (2H, s), 1.25˜1.73 (4H, m), 2.06˜2.92 (11H, m),7.02˜7.36 (5H, m).

N-Methyl-N-(2-(4-methoxyphenyl)ethyl)-1,4-diaminobutane ##STR66##

colorless oil.

boiling point (° C.): 147˜155 (˜1 mmHg).

NMR (CDCl₃) δ; 1.27 (2H, s), 1.34˜1.68 (4H, m), 2.07˜2.85 (11H, m), 3.76(3H, s), 6.69˜6.88 (2H, m), 6.97˜7.17 (2H, m).

N-Methyl-N-(2-(3-methoxyphenyl)ethyl)-1,4-diaminobutane ##STR67##

colorless oil

boiling point (° C.): 144˜150 (˜1 mmHg).

NMR (CDCl₃) δ;

1.40˜1.74 (6H, m), 2.30 (3H, s), 2.40 (2H, t, J=7.2 Hz), 2.57˜2.63 (2H,m), 2.67˜2.78 (4H, m), 3.80 (3H, s), 6.72˜6.76 (1H, m), 6.77˜6.81 (1H,m), 7.17˜7.23 (1H, m), 7.25˜7.27 (1H, m).

N-Methyl-N-(2-(4-methylphenyl)ethyl)-1,4-diaminobutane ##STR68##

colorless oil.

boiling point (° C.): 128˜132 (0.5 mmHg).

NMR (CDCl₃) δ; 1.40˜1.56 (6H, m), 2.29 (3H, s), 2.31 (3H, s), 2.40 (2H,dt, J=0.8 Hz, 7.6 Hz), 2.55˜2.61 (2H, m), 2.67˜2.76 (4H, m), 7.09 (4H,s).

N-Methyl-N-(2-(4-methoxy-3-methylphenyl)-ethyl)-1,4-diaminobutane##STR69##

colorless oil.

boiling point (° C.): 148˜153 (˜1 mmHg).

NMR (CDCl₃) δ; 1.20 (2H, s), 1.30˜1.62 (4H, m), 2.20˜2.82 (11H, m), 3.76(3H, s), 6.66 (1H, d, J=9 Hz), 6.80˜7.00 (2H, m).

PREPARATIVE EXAMPLE 23N-Methyl-N-(2-(3,4-dimethoxyphenyl)ethyl)-1,5-diaminopentane ##STR70##

2.5 g of N-methyl-(2-(3,4-dimethoxyphenyl)ethyl)amine was dissolved in25 ml of N,N-dimethylformamide, followed by the addition of 1.95 g ofanhydrous potassium carbonate and 1.65 ml of 4-bromovaleronitrile. Theobtained mixture was reacted at a room temperature for 16 hours,followed by the addition of water. The obtained mixture was extractedwith ethyl acetate. The ethyl acetate layer was washed with water and asaturated aqueous solution of common salt, dried over anhydrouspotassium carbonate and distilled to remove the solvent. 40 ml ofethanol, 3.2 ml of concentrated hydrochloric acid and 0.3 g of platinumoxide were added to the obtained residue to carry out hydrogenation at aroom temperature under 3 kg/cm² for 6 hours. The catalyst was filteredout and the filtrate was concentrated under a reduced pressure, followedby the addition of concentrated aqueous ammonia. The obtained mixturewas extracted with chloroform. The chloroform phase was dried overanhydrous potassium carbonate and distilled to remove the solvent. Theresidue was purified by silica gel column chromatography [solvent:dichloromethane/methanol/concentrated aqueous ammonia (100:10:1)] toobtain 1.95 g of the title compound as a yellow oil (yield: 55%).

NMR (CDCl₃) δ; 1.2˜1.9 (8H, m), 2.2˜2.9 (11H, m), 3.83 (3H, s), 3.86(3H, s), 6.8˜6.9 (3H, m).

PREPARATIVE EXAMPLE 243-((N-Methyl-N-(2-(3,4-dimethoxyphenyl)ethyl)amino)-2-methylpropylchloride ##STR71##

8.0 g of N-methyl-(2-(3,4-dimethoxyphenyl)ethyl)amine was dissolved in120 ml of N,N-dimethylformamide, followed by the addition of 6.8 g ofanhydrous potassium carbonate and 14.4 ml of1-bromo-3-chloro-2-methylpropane. The obtained mixture was reacted at aroom temperature for 12 hours, followed by the addition of water. Theobtained mixture was extracted with ethyl acetate. The ethyl acetatephase was washed with water and a saturated aqueous solution of commonsalt, dried over anhydrous potassium carbonate and distilled to removethe solvent. The obtained residue was purified by silica gel columnchromatography [solvent: dichloromethane/methanol (50:1)] to obtain 4.67g of the title compound as a pale yellow oil (yield: 40%).

NMR (CDCl₃) δ; 0.98 (3H, d, J=6.8 Hz), 1.6˜2.8 (10H, m), 3.3˜3.5 (2H,m), 3.83 (3H, s), 3.85 (3H, s), 6.6˜6.8 (3H, m).

PREPARATIVE EXAMPLE 254-((N-Methyl-N-(2-(3,4-dimethoxyphenyl)ethyl)amino)-3-methylpropionitrile##STR72##

4.67 g of3-((N-methyl-N-(2-(3,4-dimethoxyphenyl)ethyl)-amino-2-methylpropylchloride was dissolved in 40 ml of acetonitrile, followed by theaddition of 2.13 g of potassium cyanide and 0.1 g of 18-crown-6. Theobtained mixture was heated under reflux for 40 hours, followed by theaddition of water. The obtained mixture was extracted with ethylacetate. The ethyl acetate phase was washed with water and a saturatedaqueous solution of common salt, dried over anhydrous magnesium sulfateand distilled to remove the solvent. The residue was purified by silicagel column chromatography [solvent: n-hexane/ethyl acetate (1:1)] toobtain 3.93 g of the title compound as a pale yellow oil (yield: 87%).

NMR (CDCl₃) δ; 1.02 (3H, d, J=6.5 Hz), 1.7˜2.8 (12H, m), 3.82 (3H, s),3.84 (3H, s), 6.6˜6.9 (3H, m).

PREPARATIVE EXAMPLE 264-((N-Methyl-N-(2-(3,4-dimethoxyphenyl)ethyl)amino-3-methylbutylamine##STR73##

3.93 g of4-((N-methyl-N-(2-(3,4-dimethoxyphenyl)ethyl)amino)-3-methylpropionitrilewas dissolved in 40 ml of ethanol to obtain a solution. 3.6 ml ofconcentrated hydrochloric acid and 0.3 g of platinum oxide were added tothe solution to carry out hydrogenation at a room temperature under 3kg/cm² for 7 hours. The catalyst was filtered out and the filtrate wasconcentrated under a reduced pressure, followed by the addition ofconcentrated aqueous ammonia. The obtained mixture was extracted withchloroform. The extract was dried over anhydrous potassium carbonate anddistilled to remove the solvent. The obtained residue was purified bysilica gel column chromatography [solvent:dichloromethane/methanol/concentrated aqueous ammonia (100:10:1)] toobtain 2.98 g of the title compound as a pale yellow oil (yield: 75%).

NMR (CDCl₃) δ; 0.88 (3H, d, J=6.5 Hz), 1.0˜2.0 (5 H, m), 2.1˜2.3 (5H,m), 2.4˜2.8 (6H, m), 3.82 (3H, s), 3.84 (3H, s), 6.6˜6.9 (3H, m).

PREPARATIVE EXAMPLE 27 Methyl4-((N-methyl-N-(3,4-dimethoxyphenylacetyl))amino)pentanoate ##STR74##

4.5 g of 1,5-dimethyl-2-pyrrolidinone was dissolved in 120 ml of 1Nhydrochloric acid to obtain a solution. This solution was heated underreflux for 4 hours, cooled and distilled under a reduced pressure toremove the water. The obtained residue was passed through a Dowexion-exchange column to obtain an amino carboxylic acid. This aminocarboxylic acid was dissolved in 100 ml of water-containing acetone(water content: 50%), followed by the addition of 3.02 g of potassiumcarbonate. The obtained mixture was cooled to 0° C., followed by theslow dropwise addition of a solution of 8.54 g of3,4-dimethoxyphenylacetyl chloride in 10 ml of acetone. The obtainedmixture was stirred at a room temperature overnight and distilled undera reduced pressure to remove the acetone. The obtained aqueous phase waswashed with ethyl acetate and the pH of the aqueous phase was adjustedto 2 to 3 with 2N hydrochloric acid. The resulting aqueous phase wasextracted with chloroform thrice. The chloroform phase was distilledunder a reduced pressure to remove the chloroform. 50 ml of ether wasadded to the residue. The obtained mixture was cooled to 0° C., followedby the gradual addition of a solution of diazomethane in ether. Theobtained mixture was stirred at a room temperature for one hour.Excessive diazomethane was decomposed with acetic acid. The resultingmixture was extracted with ethyl acetate. The ethyl acetate phase wasdried over anhydrous sodium sulfate and distilled to remove the solvent.The obtained residue was purified by silica gel column chromatography[solvent: chloroform/methanol (100:1)] to obtain 2.05 g of the tilecompound as a pale yellow oil (yield: 16%).

NMR (CDCl₃) δ; 1.09, 1.22 (total 3H, d, J=7 Hz), 1.54˜1.90 (2H, m),2.00˜2.46 (2H, m), 2.72, 2.74 (total 3H, s), 3.41˜3.74 (5H, m), 3.82(6H, s), 3.94˜4.20, 4.60˜4.87 (total 1H, m), 6.71˜6.85 (3H, m).

PREPARATIVE EXAMPLE 284-((N-Methyl-N-(3,4-dimethoxyphenylacetyl))amino)pentanamide ##STR75##

2.05 g of methyl4-((N-methyl-N-(3,4-dimethoxyphenylacetyl))amino)pentanoate wasdissolved in 20 ml of concentrated aqueous ammonia, followed by theaddition of 3.3 g of ammonium chloride. The obtained mixture was stirredat a room temperature overnight and extracted with chloroform. Thechloroform phase was dried over anhydrous sodium sulfate and distilledto remove the solvent. The residue was purified by silica gel columnchromatography [solvent: chloroform/methanol (50:1)] to obtain 1.20 g ofthe title compound as a pale yellow oil (yield: 63%).

NMR (CDCl₃) δ; 0.97, 1.10 (total 3H, each t, J=7 Hz), 1.53˜1.88 (2H, m),1.88˜2.10 (2H, m), 2.72, 2.77 (total 3H, each s), 3.56˜3.72 (2H, m),3.84 (6H, s), 3.90˜4.19, 4.50˜4.88 (total 1H, each m), 6.68˜6.88 (3H,m).

PREPARATIVE EXAMPLE 294-(N-Methyl-N-(2-(3,4-dimethoxyphenyl)ethyl)amino)pentylamine ##STR76##

0.2 g of lithium aluminum hydride was suspended in 10 ml oftetrahydrofuran to obtain a suspension. 10 ml of a solution of 0.4 g of4-((N-methyl-N-(3,4-dimethoxyphenylacetyl))amino)pentanamide intetrahydrofuran was dropwise added to the suspension at a roomtemperature. The obtained mixture was heated under reflux for 4 hoursand cooled. 1 ml of a 6N aqueous solution of sodium hydroxide and 1 mlof water were successively added to the resulting mixture, followed bystirring. The insoluble matter thus precipitated was filtered out andthe filtrate was distilled under a reduced pressure. The residue waspurified by silica gel column chromatography [solvent:dichloromethane/methanol/concentrated aqueous ammonia (1000:100:1)] toobtain 0.2 g of the title compound as a pale yellow oil (yield: 55%).

NMR (CDCl₃) δ; 0.95 (3, d, J=7 Hz), 1.48˜1.85 (4H, m), 2.15 (3H, s),2.47˜2.92 (6H, m), 3.84 (6H, s), 6.70˜6.90 (3H, m).

PREPARATIVE EXAMPLE 30N-(4-((N'-(2-(3,4-Dimethoxyphenyl)ethyl)-N'-methyl)amino)-2-butyl)phthalimide##STR77##

58.5 g of N-methyl-2-(3,4-dimethoxyphenyl)ethylamine was slowly dropwiseadded to 23.1 g of methyl vinyl ketone under cooling with ice. Theobtained mixture was allowed to stand at a room temperature overnightand dissolved in 500 ml of methanol to obtain a solution. 14 g of sodiumborohydride was added to the solution in portions under cooling withice. The obtained mixture was stirred at a room temperature for 2 hoursand excessive reagent was decomposed with acetone. The methanol wasdistilled off under a reduced pressure and the residue was extractedwith ethyl acetate. The ethyl acetate phase was dried over anhydroussodium sulfate, freed from the solvent and purified by silica gel columnchromatography [solvent: chloroform/methanol (100:1)] to obtain 70 g of4-((N-(2-(3,4-dimethoxyphenyl)ethyl)-N-methyl)amino)-2-butanol (yield:87%).

4.74 g of4-((N-(2-(3,4-dimethoxyphenyl)ethyl)-N-methyl)amino)-2-butanol, 4.65 gof triphenylphosphine and 2.61 g of phthalimide were dissolved in 50 mlof tetrahydrofuran. The obtained solution was cooled to 0° C., followedby the dropwise addition of 3.09 g of diethyl azodicarboxylate. Theobtained mixture was stirred at a room temperature overnight andfiltered. The filtrate was concentrated under a reduced pressure. Theresidue was made acidic by the addition of 1N hydrochloric acid andwashed with ethyl acetate. The aqueous phase was made basic with lithiumhydroxide and extracted with chloroform. The chloroform phase was driedover anhydrous sodium sulfate and distilled to remove the solvent. Theresidue was purified by silica gel column chromatography [solvent:chloroform/methanol (100:1)] to obtain 4.2 g of the title compound as apale yellow oil (yield: 60%).

NMR (CDCl₃) δ; 1.50 (3H, d, J=7 Hz), 2.02 (3H, s), 2.24 (3H, s),2.14˜2.68 (8H, m), 3.86 (3H, s), 3.89 (3H, s), 4.34˜4.61 (1H, m),6.62˜6.88 (3H, m), 7.64˜7.96 (4H, m).

PREPARATIVE EXAMPLE 314-((N-Methyl-N-(2-(3,4-dimethoxyphenyl)ethyl)amino)-2-butylamine##STR78##

4.8 g ofN-(4-((N'-(2-(3,4-dimethoxyphenyl)ethyl)-N'-methyl)amino)-2-butyl)phthalimidewas dissolved in 50 ml of ethanol, followed by the addition of 0.73 g ofhydrazine monohydrate. The obtained mixture was heated under reflux for2 hours and cooled. The formed precipitate was filtered out and thefiltrate was concentrated under a reduced pressure. The residue waspurified by silica gel column chromatography [solvent:chloroform/methanol/concentrated aqueous ammonia (250:25:1)] to obtain2.58 g of the title compound as a pale yellow oil (yield: 80%).

NMR (CDCl₃) δ; 1.07 (3H, d, J=6 Hz), 1.32˜1.89 (4H, m), 2.28 (3H, s),2.32˜3.07 (7H, m), 3.81 (3H, s), 3.84 (3H, s), 6.55˜6.85 (3H, m).

PREPARATIVE EXAMPLE 32N-Methyl-N-(4-(tert-butyldimethylsiloxy)-butan-2-yl)-[2-(3,5-dimethoxyphenyl)ethyl]amine##STR79##

2.16 g of methanesulfonyl chloride was slowly added to 30 ml of asolution of 3.50 g of 4-(tertbutyldimethylsiloxy)butan-2-ol and 1.90 gof triethylamine in ether under cooling with ice. After 30 minutes,water was added to the obtained mixture, followed by the extraction withether. The ether phase was dried over anhydrous sodium sulfate andfiltered. The filtrate was distilled to remove the ether. The residuewas dissolved in 30 ml of acetonitrile, followed by the addition of 3.37g of N-methyl-[2-(3,5-dimethyoxypheny)ethyl]amine and 3.48 g ofpotassium carbonate. The obtained mixture was heated under reflux for 12hours and cooled to precipitate a crystal. The crystal was filtered outand the filtrate was concentrated under a reduced pressure and extractedwith ether thrice. The ether phase was washed with an aqueous solutionof common salt, dried over anhydrous sodium-sulfate and filtered. Thefiltrate was concentrated under a reduced pressure and purified bysilica gel column chromatography [solvent: chloroform/methanol (100:1)]to obtain 3.33 g of the title compound as a yellow oil (yield: 56%).

NMR (CDCl₃) δ; 0.04 (6H, s), 0.89 (9H, s), 0.95 (3H, d, J=6.6 Hz),1.38˜1.92 (2H, m), 2.25 (3H, s), 2.40˜2.96 (5H, m), 3.58 (2H, t, J=6.6Hz), 3.77 (6H, s), 6.20˜6.39 (3H, m).

PREPARATIVE EXAMPLE 333-(N-Methyl-N-(2-(3,5-dimethoxyphenyl)ethyl)amino)butylamine ##STR80##

3.33 g ofN-methyl-N-(4-(tert-butyldimethylsiloxy)-butan-2-yl)-[2-(3,5-dimethoxyphenyl)ethyl]aminewas dissolved in 13 ml of tetrahydrofuran to obtain a solution. 13 ml ofa solution of tetra-n-butylammonium fluoride in tetrahydrofuran (1mmol/ml) was slowly added dropwise to the solution. The obtained mixturewas stirred at a room temperature for 3 hours and distilled to removethe solvent. The residue was extracted with ether thrice and the etherphase was dried over anhydrous sodium sulfate and concentrated under areduced pressure. The residue was dissolved in 25 ml of tetrahydrofuran,followed by the addition of 1.29 g of phthalimide and 2.29 g oftriphenylphosphine. 1.52 g of diethyl azodicarboxylate was slowly addedto the obtained mixture at a room temperature. The obtained mixture wasstirred overnight and distilled to remove the solvent. The residue wasmade acidic with 0.5N hydrochloric acid and washed with ether. Theaqueous phase was made basic with lithium hydroxide and extracted withethyl acetate. The ethyl acetate phase was dried over anhydrous sodiumsulfate and the filtrate was concentrated under a reduced pressure toobtain a residue. This residue was dissolved in 20 ml of ethanol,followed by the addition of 200 mg of hydrazine monohydrate. Theobtained mixture was heated under reflux for 2 hours and cooled. Thewhite precipitate thus formed was filtered out and the filtrate wasconcentrated under a reduced pressure, followed by the addition of 20 mlof a 10% solution of sodium hydroxide. The obtained mixture wasextracted with chloroform thrice. The chloroform phase was washed with asaturated aqueous solution of common salt, dried over anhydrous sodiumsulfate and concentrated under a reduced pressure to obtain 830 mg ofthe title compound as a yellow oil (yield: 36%).

NMR (CDCl₃) δ; 0.92 (3H, d, J=6.3 Hz), 1.18˜2.08 (4H, m), 2.24 (3H, s),2.52˜2.92 (7H, m), 3.77 (6H, s), 6.20˜6.36 (3H, m).

PREPARATIVE EXAMPLE 34N-Methyl-N-(2-(3-chloro-4-methoxyphenyl)ethyl)-1,4-diaminobutane##STR81##

A mixture comprising 5.00 g ofN-methyl-(2-(3-chloro-4-methoxyphenyl)ethylamine, 9.49 g ofN-(4-bromobutyl)phthalimide, 4.16 g of anhydrous potassium carbonate and50 ml of N,N-dimethylformamide was stirred at a room temperature for 14hours, followed by the addition of water. The obtained mixture wasextracted with ethyl acetate and the ethyl acetate phase was washed withwater and a saturated aqueous solution of common salt, dried overanhydrous magnesium sulfate and concentrated, followed by the additionof 50 ml of ethanol and 1.5 ml of hydrazine monohydrate. The obtainedmixture was heated under reflux for 2 hours, cooled by allowing to standand filtered to remove insoluble matter. The filtrate was distilled toobtain 3.16 g of the title compound as a colorless oil (yield: 47%).

boiling point (° C.): 167˜172 (˜1 mmHg).

NMR (CDCl₃) δ; 1.20 (2H, s), 1.30˜1.64 (4H, m), 2.20˜2.84 (11H, m), 3.82(3H, s), 6.77 (1H, d, J=8.6 Hz), 6.98 (1H, dd, J=2.2 Hz, 8.6 Hz), 8.15(1H, d, J=2.2 Hz).

PREPARATIVE EXAMPLE 35

The following compounds were prepared in a similar manner to that ofPreparative Example 34.

N-Methyl-N-(2-(4-chlorophenyl)ethyl)-1,4-diaminobutane ##STR82##

colorless oil.

boiling point (° C.): 143˜147 (˜1 mmHg).

NMR (CDCl₃) δ; 1.25˜1.72 (6H, m), 2.28 (3H, s), 2.39 (2H, t, J=7.6 Hz),2.54˜2.60 (2H, m), 2.66˜2.76 (4H, m), 7.12 (2H, d, J=8.8 Hz), 7.24 (2H,d, J=8.8 Hz).

N-Methyl-N-(2-(3,4-dichlorophenyl)ethyl)-1,4-diaminobutane ##STR83##

colorless oil.

boiling point (° C.): 163˜165 (˜1 mmHg).

NMR (CDCl₃) δ; 1.36˜1.68 (6H, m), 2.27 (3H, s), 2.38 (2H, t, J=7.6 Hz),2.54˜2.59 (2H, m), 2.67˜2.74 (4H, m), 7.03 (1H, dd, J=2.4 Hz, 8.4 Hz),7.24 (1H, d, J=2.4 Hz), 7.33 (1H, d, J=8.4 Hz).

EXAMPLE 1(E)-[N-(3-((N'-(2-(3,4-Dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl]-4-(4-(N³-methyl-N² -cyanoguanidino)phenyl)-3-butenamide ##STR84##

0.8 g of (E)-4-(4-(N³ -methyl-N² -cyanoguanidino)phenyl)-3-butenoicacid, 0.86 g ofN-methyl-N-(2-(3,4-dimethoxyphenyl)ethyl)-1,3-diaminopropane, 0.71 g ofN,N-dicyclohexylcarbodiimide and 0.46 g of N-hydroxybenzotriazole wereadded to 7 ml of acetonitrile. The obtained mixture was stirred at 70°C. for 30 minutes and cooled, followed by the addition of dilutehydrochloric acid. The obtained mixture was filtered to remove insolublematter. The filtrate was made alkaline by the addition of potassiumcarbonate and extracted with chloroform. The chloroform phase was driedover anhydrous potassium carbonate and distilled under a reducedpressure to remove the solvent. The residue was purified by silica gelcolumn chromatography [solvent: dichloroethane/methanol/concentratedaqueous ammonia (100:100:3)] to obtain 1.09 g of the title compound as ayellow amorphous product (yield: 71%).

NMR (CDCl₃) δ; 1.5˜1.9 (2H, m), 2.23 (3H, s), 2.3˜2.9 (6H, m), 2.84 (3H,d, J=4.3 Hz), 2.98 (2H, d, J=5.8 Hz), 3.1˜3.5 (2H, m), 3.81 (6H, s),5.22 (1H, br), 6.16 (1H, dt, J=5.8 Hz, 15.1 Hz), 6.39 (1H, d, J=15.1Hz), 6.5˜6.9 (3H, m), 7.0˜7.4 (5H, m), 7.56 (1H, br).

EXAMPLE 2(E)-[N-(3-((N'-(2-(3,5-Dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl]-4-(4-(N³-methyl-N² -cyanoguanidino)phenyl)-3-butenamide ##STR85##

0.6 g of (E)-4-(4-(N³ -methyl-N² -cyanoguanidino)phenyl)-3-butenoicacid, 0.65 g ofN-methyl-N-(2-(3,5-dimethoxyphenyl)ethyl)-1,3-propanediamine, 0.53 g ofN,N-dicyclohexylcarbodiimide and 0.35 g of N-hydroxybenzotriazole wereadded to 6 ml of acetonitrile. The obtained mixture was stirred at 70°C. for 30 minutes, cooled and filtered to remove insoluble matter. Thefiltrate was concentrated under a reduced pressure, made alkaline by theaddition of a dilute aqueous solution of potassium carbonate andextracted with chloroform. The chloroform phase was dried over anhydrouspotassium carbonate and distilled under a reduced pressure to remove thesolvent. The residue was purified by silica gel column chromatography[solvent: dichloromethane/methanol/concentrated aqueous ammonia(500:50:1)] to obtain 0.92 g of the title compound as a pale yellowamorphous product (yield: 81%).

NMR (CDCl₃) δ; 1.5˜1.8 (2H, m), 2.20 (3H, s), 2.3˜2.7 (6H, m), 2.84 (3H,d, J=4.8 Hz), 2.99 (2H, d, J=6.2 Hz), 3.1˜3.5 (2H, m), 5.16 (1H, br),6.0˜6.5 (5H, m), 7.0˜7.4 (5H, m), 7.54 (1H, br).

EXAMPLE 3(E)-[N-(4-((N'-(2-(3,5-Dimethoxyphenyl)ethyl)-N'-methyl)amino)butyl]-4-(4-(1,4-dihydro-4-oxo-1-pyridyl)phenyl)-3-butenamide##STR86##

5.32 g of (E)-4-(4-(1,4-dihydro-4-oxo-1-pyridyl)phenyl)-3-butenoic acid,5.85 g of N-methyl-N-(2-(3,5-dimethoxyphenyl)ethyl)-1,4-diaminobutane,4.54 g of N,N-dicyclohexylcarbodiimide and 2.97 g ofN-hydroxybenzotriazole were added to 60 ml of acetonitrile. The obtainedmixture was stirred at 60° to 70° C. for 40 minutes and cooled, followedby the addition of dilute hydrochloric acid. The insoluble matter thusformed was filtered out and the filtrate was washed with ethyl acetate,followed by the addition of dilute aqueous ammonia. The obtained mixturewas extracted with chloroform. The chloroform phase was dried overanhydrous potassium carbonate and distilled under a reduced pressure.The residue was purified by silica gel column chromatography [solvent:methanol/concentrated aqueous ammonia (200:20:1)] to obtain 6.75 g ofthe title compound as a pale yellow oil (yield: 67%).

NMR (CDCl₃) δ; 1.4˜1.7 (4H, m), 2.2˜2.8 (9H, m), 3.0˜3.4 (4H, m), 3.76(6H, s), 6.1˜6.8 (8H, m), 7.1˜7.6 (6H, m).

EXAMPLE 4(E)-[N-(4-((N'-(2-(3,5-Dimethoxyphenyl)ethyl)-N'-methyl)amino)butyl]-4-(4-(1H-imidazol-1-yl)phenyl)-3-butenamide##STR87##

3.42 g of (E)-4-(4-(1H-imidazol-1-yl)phenyl)-3-butenoic acid, 4.39 g ofN-methyl-N-(2-(3,5-dimethoxyphenyl)ethyl)-1,4 diaminobutane, 3.40 g ofN,N-dicyclohexylcarbodiimide and 2.23 g of N-hydroxybenzotriazole wereadded to 50 ml of acetonitrile. The obtained mixture was stirred at 70°C. for 40 minutes, cooled and filtered to remove insoluble matter.Dilute aqueous ammonia was added to the filtrate, followed by theextraction with chloroform. The chloroform phase was dried overanhydrous potassium carbonate and distilled under a reduced pressure toremove the solvent. The residue was purified by silica gel columnchromatography [solvent: dichloromethane/methanol/concentrated aqueousammonia (1000:100:3)] to obtain 5.41 g of the title compound as a paleyellow oil (yield: 76%).

NMR (CDCl₃) δ; 1.4˜1.7 (4H, m), 2.3˜2.8 (9H, m), 3.0˜3.5 (4H, m), 3.76(6H, s), 6.1˜6.8 (6H, m), 7.1˜7.5 (6H, m), 7.83 (1H, s).

EXAMPLE 5(E)-[N-(4-((N'-(2-(3,4-Dimethoxyphenyl)ethyl)-N'-methyl)amino)pentyl]-4-(4-(1,4-dihydro-4-oxo-1-pyridyl)phenyl)-3-butenamide##STR88##

0.35 g of (E)-4-(4-(1,4-dihydro-4-oxo-1-pyridyl)phenyl)-3-butenoic acid,0.2 g of4-[(N-methyl-N-(2-(3,4-dimethoxyphenyl)ethyl))amino]pentylamine, 0.4 gof N,N-dicyclohexylcarbodiimide and 0.26 g of N-hydroxybenzotriazolewere added to 10 ml of acetonitrile. The obtained mixture was stirred at60° C. for 30 minutes, cooled and filtered to remove insoluble matter.The filtrate was concentrated under a reduced pressure and made acidicby the addition of dilute hydrochloric acid. The aqueous phase waswashed with ethyl acetate, followed by the addition of a dilute aqueoussolution of lithium hydroxide. The obtained mixture was extracted withchloroform. The chloroform phase was dried over anhydrous sodium sulfateand distilled under a reduced pressure. The residue was purified bysilica gel column chromatography [solvent:dichloromethane/methanol/concentrated aqueous ammonia (400:40:1)] toobtain 0.3 g of the title compound as a pale yellow oil (yield: 81%).

NMR (CDCl₃) δ; 0.97 (3H, d, J=6 Hz), 1.20˜1.96 (4H, m), 2.32 (3H, s),2.52˜2.96 (5H, m), 3.06˜3.64 (4H, m), 3.82 (3H, s), 3.84 (3H, s),6.30˜6.92 (6H, m), 7.08˜7.70 (8H, m).

EXAMPLE 6(E)-N-[(4-((N'-(2-(3,5-Dimethoxyphenyl)ethyl)-N'-methyl)amino)butyl]-4-[4-(4-nitro-1H-imidazol-1-yl)phenyl]-3-butenamide##STR89##

585 mg of N-methyl-N-[2-(3,5-dimothoxyphenyl)ethyl]-1,4-diaminobutanewas added to a suspension of 546 mg of(E)-4-[(4-nitro-1H-imidazol-1-yl)phenyl]-3-butenoic acid, 453 mg ofN,N'-dicyclohexylcarbodiimide and 300 mg of N-hydroxybenzotriazole in 30ml of dioxane at a room temperature under stirring. The obtainedreaction mixture was stirred at 40° to 50° C. for about one hour andpoured into water, followed by the addition of ethyl acetate. Theinsoluble matter thus formed was filtered out and the organic phase wasseparated, washed with an aqueous solution of sodium hydrogencarbonateand water, dried over magnesium sulfate and purified by silica gelcolumn chromatography [solvent: dichloromethane/ethanol] to obtain 440mg of the title compound as a lightly red oil.

NMR (CDCl₃) δ; 1.5˜1.7 (4H, m), 2.32 (3H, s), 2.3˜2.6 (2H, m), 2.6˜2.9(4H, m), 3.1˜3.6 (4H, m), 3.76 (6H, s), 6.24˜6.7 (6H, m), 7.24˜7.6 (4H,m), 7.76 (1H, d, J=1 Hz), 8.08 (1H, d, J=1 Hz).

EXAMPLE 7(E)-N-[4-((N'-(2-(3,5-Dimethoxyphenyl)ethyl)-N'-methyl)amino)butyl]-4-(2-(1H-imidazol-1-yl)thiophen-5-yl)-3-butenamide##STR90##

0.48 g of 4-(2-(1H-imidazol-1-yl)thiophen-5-yl)-3-butenoic acid, 0.51 gof N,N'-dicyclohexylcarbodiimide, 0.33 g of N-htdroxybenzotriazole, 0.65g of N-2-((3,5-dimethoxyphenyl)ethyl)-N-methyl-1,4-diaminobutane and anacetonitrile (50 ml)/water (10 ml) mixture were together stirred at 60°C. for 30 minutes to precipitate a crystal. This crystal was filteredout and the filtrate was concentrated under a reduced pressure andpurified by silica gel column chromatography to obtain 0.95 g of thetitle compound as a yellow oil.

NMR (CDCl₃) δ; 1.4˜1.7 (4H, m), 2.29 (3H, s), 2.3˜2.8 (6H, m), 3.07 (2H,d, J=6.5 Hz), 3.1˜3.4 (2H, m), 3.77 (6H, s), 6.12 (1H, dt, J=16.0 Hz,6.5 Hz), 6.3˜6.4 (3H, m), 6.53 (1H, d, J=16.0 Hz), 6.6 (1H, m), 6.7˜6.9(2H, m), 7.1˜7.2 (2H, m), 7.7 (1H, m).

EXAMPLES 8 TO 52

The compounds which will be described in Examples 8 to 52 were preparedin a similar manner to that of Example 1.

Namely, the same procedure as that of Example 1 was repeated except thatthe (E)-4-(4-(N³ -methyl-N² -cyanoguanidino)phenyl)-3-butenoic acid wasreplaced by the corresponding 4-substituted phenyl-3-butenoic acid andthe N-methyl-N-(2-(3,4-dimethoxyphenyl)ethyl)-1,3-diaminopropane wasreplaced by the corresponding substituted diaminoalkane to obtain thecompounds which will be described below.

EXAMPLE 8(E)-[N-(3-((N'-(2-(3,5-Dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl]-4-(4-(1,4-dihydro-4-oxo-1-pyridyl)phenyl)-3-butenamide##STR91##

pale yellow oil.

NMR (CDCl₃) δ; 1.5˜1.8 (2H, m), 2.22 (3H, s), 2.3˜2.7 (6H, m), 3.07 (2H,d, J=5.7 Hz), 3.1˜3.5 (2H, m), 3.75 (6H, s), 6.0˜6.6 (7H, m), 7.0˜7.6(7H, m).

EXAMPLE 9(E)-[N-(3-((N'-(2-(3,4-Dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl]-4-(4-(N²-methylthioureido)phenyl)-3-butenamide ##STR92##

pale yellow oil.

NMR (CDCl₃) δ; 1.5˜1.9 (2H, m), 2.24 (3H, s), 2.3˜2.7 (6H, m), 3.00 (3H,d, J=6.2 Hz), 3.09 (2H, d, J=4.8 Hz), 3.2˜3.5 (2H, m), 3.83 (6H, s),6.08 (1H, dt, J=4.8 Hz, 15.1 Hz), 6.2˜6.5 (2H, m), 6.5˜6.8 (3H, m),7.0˜7.4 (5H, m), 8.34 (1H, br s).

EXAMPLE 10(E)-[N-(4-((N'-(2-(3,4-Dimethoxyphenyl)ethyl)-N'-methyl)amino)butyl]-4-(4-(1H-imidazol-1-yl)phenyl)-3-butenamide##STR93##

pale yellow oil.

NMR (CDCl₃) δ; 1.4˜1.8 (4H, m), 2.2˜2.8 (9H, m), 2.9˜3.4 (4H, m), 3.84(3H, s), 3.86 (3H, s), 6.24 (1H, dt, J=6.2 Hz, 15.8 Hz), 6.4˜6.8 (5H,m), 7.1˜7.5 (6H, m), 7.83 (1H, s).

EXAMPLE 11(E)-[N-(4-((N'-(2-(3,4-Dimethoxyphenyl)ethyl)-N'-methyl)amino)butyl]-4-(4-(1,4-dihydro-4-oxo-1-pyridyl)phenyl)-3-butenamide##STR94##

pale yellow oil.

NMR (CDCl₃) δ; 1.4˜1.8 (4H, m), 2.2˜2.9 (9H, m), 3.0˜3.4 (4H, m), 3.82(3H, s), 3.84 (3H, s), 6.2˜6.6 (4H, m), 6.6˜7.0 (4H, m), 7.1˜7.7 (6H,m).

EXAMPLE 12(E)-[N-(4-((N'-(2-(3,4-Dimethoxyphenyl)ethyl)-N'-methyl)amino)butyl]-4-(4-(N³-methyl-N² -cyanoguanidino)phenyl)-3-butenamide ##STR95##

pale yellow amorphous product.

NMR (CDCl₃) δ; 1.35˜1.74 (4H, m), 2.31 (3H, s), 2.34˜2.76 (6H, m), 2.85(3H, d, J=4.8 Hz), 2.96˜3.34 (4H, m), 3.83 (3H, s), 3.84 (3H, s),5.26˜5.53 (1H, m), 6.20 (1H, dt, J=5.7 Hz, 15.8 Hz), 6.44 (1H, d, J=15.8Hz), 6.51˜6.82 (4H, m), 6.99˜7.35 (4H, m), 7.53˜7.82 (1H, m).

EXAMPLE 13(E)-[N-(4-((N'-(2-(3,5-Dimethoxyphenyl)ethyl)-N'-methyl)amino)butyl]-4-(4-(N³-methyl-N² -cyanoguanidino)phenyl)-3-butenamide ##STR96##

lightly orange-colored amorphous product.

NMR (CDCl₃) δ; 1.32˜1.72 (4H, m), 2.29 (3H, s), 2.30˜2.75 (6H, m), 2.85(3H, d, J=4.8 Hz), 2.98˜3.31 (4H, m), 3.76 (6H, s), 5.26˜5.47 (3H, m),5.98˜6.37 (5H, m), 6.53˜6.71 (1H, m), 6.97˜7.35 (4H, m), 7.51˜7.82 (1H,m).

EXAMPLE 14(E)-[N-(4-((N'-(2-(3,4-Dimethoxyphenyl)ethyl)-N'-methyl)amino)-3-methylbutyl]-4-(4-(1H-imidazol-1-yl)phenyl)-3-butenamide##STR97##

pale yellow oil.

NMR (CDCl₃) δ; 0.94 (3H, d, J=6.5 Hz), 1.3˜1.9 (3H, m), 2.1˜2.4 (5H, m),2.5˜2.9 (4H, m), 3.0˜3.5 (4H, m), 3.82 (3H, s), 3.84 (3H, s), 6.28 (1H,dt, J=6.1 Hz, 15.5 Hz), 6.56 (1H, d, J=15.5 Hz), 6.6˜6.9 (3H, m),7.0˜7.5 (7H, m), 7.84 (1H, br s).

EXAMPLE 15(E)-[N-(4-((N'-(2-(3,4-Dimethoxyphenyl)ethyl)-N'-methyl)amino)-2-butyl]-4-(4-(1,4-dihydro-4-oxo-1-pyridyl)phenyl)-3-butenamide##STR98##

pale yellow oil.

NMR (CDCl₃) δ; 1.20 (3H, d, J=7 Hz), 1.46˜1.84 (2H, m), 2.26 (3H, s),2.36˜2.83 (6H, m), 3.04 (2H, d, J=6 Hz), 3.80 (3H, s), 3.83 (3H, s),3.92˜4.22 (1H, m), 6.28˜6.84 (7H, m), 7.04˜7.80 (7H, m).

EXAMPLE 16(E)-[N-(3-((N'-(2-(3,4-Dimethoxyphenyl)ethyl)-N'-methyl)amino)butyl]-4-(4-(1,4-dihydro-4-oxo-1-pyridyl)phenyl)-3-butenamide##STR99##

pale yellow oil.

NMR (CDCl₃) δ; 0.94 (3H, d, J=7 Hz), 1.34˜1.89 (2H, m), 2.18 (3H, s),2.34˜2.82 (4H, m), 2.92˜3.64 (5H, m), 3.79 (3H, s), 3.82 (3H, s),6.18˜6.78 (5H, m), 7.00˜7.66 (7H, m).

EXAMPLE 17(E)-[N-(3-((N'-(2-(3,5-Dimethoxyphenyl)ethyl)-N'-methyl)amino)butyl]-4-(4-(1,4-dihydro-4-oxo-1-pyridyl)phenyl)-3-butenamide##STR100##

pale yellow oil.

NMR (CDCl₃) δ; 0.92 (3H, d, J=6.6 Hz), 1.2˜1.9 (2H, m), 2.16 (3H, s),2.3˜3.3 (8 H, m), 3.3˜3.7 (1H, m), 3.75 (6H, s), 6.1˜6.6 (7H, m),7.0˜7.3 (3H, m), 7.3˜7.6 (4H, m).

EXAMPLE 18(E)-[N-(3-((N'-(2-(3,4-Dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl]-4-(4-(N²-cyanopropanamidino)phenyl)-3-butenamide ##STR101##

m.p (° C.): 137 to 138.

    ______________________________________                                        elemental analysis as C.sub.28 H.sub.37 N.sub.5 O.sub.3 :                                C          H      N                                                ______________________________________                                        calculated (%)                                                                             68.40        7.59   14.25                                        found (%)    68.65        7.61   14.48                                        ______________________________________                                    

NMR (CDCl₃) δ; 1.40 (3H, t, J=7.5 Hz), 1.5˜1.9 (2H, m), 2.24 (3H, s),2.4˜2.9 (8H, m), 2.95 (2H, d, J=5.7 Hz), 3.1˜3.5 (2H, m), 3.82 (3H, s),3.84 (3H, s), 6.00 (1H, dt, J=5.7 Hz, 15.8 Hz), 6.36 (1H, d, J=15.8 Hz),6.5˜6.9 (3H, m), 6.9˜7.2 (2H, m), 7.3˜7.6 (3H, m), 9.65 (1H, br s).

EXAMPLE 19(E)-[N-(5-((N'-(2-(3,4-Dimethoxyphenyl)ethyl)-N'-methyl)amino)pentyl]-4-(4-(1H-imidazol-1-yl)phenyl)-3-butenamide##STR102##

pale yellow oil.

NMR (CDCl₃) δ; 1.1˜1.8 (6H, m), 2.2˜2.9 (9H, m), 3.0˜3.5 (4H, m), 3.84(3H, s), 3.86 (3H, s), 5.82 (1H, m), 6.26 (1H, dt, J=5.7 Hz, 15.1 Hz),6.54 (1H, d, J=15.1 Hz), 6.6˜6.9 (3H, m), 7.0˜7.5 (6H, m), 7.83 (1H, brs).

EXAMPLE 20(E)-[N-(4-((N'-(2-(3,4-Dimethoxyphenyl)ethyl)-N'-methyl)amino)pentyl]-4-(4-(1H-imidazol-1-yl)phenyl-3-butenamide##STR103##

pale yellow oil.

NMR (CDCl₃) δ; 0.97 (3H, d, J=6 Hz), 1.24˜1.72 (4H, m), 2.31 (3H, s),2.48˜2.91 (5H, m), 3.16˜2.68 (4H, m), 3.84 (3H, s), 3.86 (3H, s),6.18˜6.92 (6H, m), 7.08˜7.56 (6H, m), 7.83 (1H, s).

EXAMPLE 21(E)-N-[4-((N'-2-Phenylethyl)-N'-methyl)amino)butyl]-4-(4-(1H-imidazol-1-yl)phenyl)-3-butenamide##STR104##

yellow oil.

NMR (CDCl₃) δ; 1.45˜1.67 (4H, m), 2.23˜2.91 (9H, m), 3.06˜3.39 (4H, m),6.31 (1H, dt, J=5.7 Hz, 15.8 Hz), 6.54 (1H, d, J=15.8 Hz), 6.79 (1H,br), 7.05˜7.51 (11H, m), 7.81 (1H, s).

EXAMPLE 22(E)-N-[4-((N'-(2-(4-Methoxyphenyl)ethyl)-N'-methyl)amino)butyl]-4-(4-(1H-imidazol-1-yl)phenyl)-3-butenamide##STR105##

pale yellow oil.

NMR (CDCl₃) δ; 1.41˜1.72 (4H, m), 2.22˜2.85 (9H, m), 3.06˜3.39 (4H, m),3.74 (3H, s), 6.29 (1H, dt, J=5.5 Hz, 15.8 Hz), 6.53 (1H, d, J=15.8 Hz),6.79 (1H, d, J=8.4 Hz), 6.89˜7.49 (9H, m), 7.81 (1H, s).

EXAMPLE 23(E)-N-[4-((N'-(2-(3-Methoxyphenyl)ethyl)-N'-methyl)amino)butyl]-4-(4-(1H-imidazol-1-yl)phenyl)-3-butenamide##STR106##

pale yellow oil.

NMR (CDCl₃) δ; 1.43˜1.63 (4H, m), 2.21˜2.87 (9H, m), 3.06˜3.38 (4H, m),3.78 (3H, s), 6.19 (1H, dt, J=5.7 Hz, 15.8 Hz), 6.54 (1H, br), 6.55 (1H,d, J=15.8 Hz), 6.65˜6.85 (2H, m), 7.07˜7.55 (8H, m), 7.82 (1H, s).

EXAMPLE 24(E)-N-[4-((N'-(2-(4-Chlorophenyl)ethyl)-N'-methyl)amino)butyl]-4-(4-(1H-imidazol-1-yl)phenyl)-3-butenamide##STR107##

pale yellow oil.

NMR (CDCl₃) δ; 1.41˜1.64 (4H, m), 2.18˜2.85 (9H, m), 3.06˜3.38 (4H, m),6.19 (1H, dt, J=5.7 Hz, 15.8 Hz), 6.55 (1H, d, J=15.8 Hz), 6.95˜7.51(11H, m), 7.82 (1H, s).

EXAMPLE 25(E)-N-[4-((N'-(2-(3,4-Dichlorophenyl)ethyl)-N'-methyl)amino)butyl]-4-(4-(1H-imidazol-1-yl)phenyl)-3-butenamide##STR108##

pale yellow oil.

NMR (CDCl₃) δ; 1.41˜1.64 (4H, m), 2.26 (3H, s), 2.30˜2.85 (6H, m),3.08˜3.36 (4H, m), 6.28 (1H, br), 6.31 (1H, dt, J=5.7 Hz, 15.8 Hz), 6.55(1H, d, J=15.8 Hz), 7.00 (1H, dd, J=2.2 Hz, 7.9 Hz), 7.11˜7.56 (8H, m),7.83 (1H, s).

EXAMPLE 26(E)-N-[4-((N'-(2-(4-Methylphenyl)ethyl)-N'-methyl)amino)butyl]-4-(4-(1H-imidazol-1-yl)phenyl)-3-butenamide##STR109##

yellow oil.

NMR (CDCl₃) δ; 1.47˜1.75 (4H, m), 2.15˜2.90 (12H, m), 3.08˜3.39 (4H, m),6.29 (1H, dt, J=5.7 Hz, 15.8 Hz), 6.55 (1H, d, J=15.8 Hz), 6.70 (1H,br), 7.06 (4H, s), 7.12˜7.63 (7H, m), 7.81 (1H, s).

EXAMPLE 27(E)-N-[4-((N'-(2-(4-Methoxy-3-methylphenyl)ethyl)-N'-methyl)amino)butyl]-4-(4-(1H-imidazol-1-yl)phenyl)-3-butenamide##STR110##

pale yellow oil.

NMR (CDCl₃) δ; 1.40˜1.75 (4H, m), 2.18 (3H, s), 2.32 (3H, s), 2.34˜2.96(6H, m), 3.13 (2H, d, J=5.7 Hz), 3.16˜3.35 (2H, m), 3.78 (3H, s), 6.26(1H, dt, J=5.7 Hz, 15.8 Hz), 6.56 (1H, d, J=15.8 Hz), 6.62˜6.98 (4H, m),7.08˜7.48 (6H, m), 7.82 (1H, s).

EXAMPLE 28 (E)-N-[4-((N'-(2-(3-Chloro-4-methoxyphenyl)ethyl)-N'-methyl)amino)butyl]-4-(4-(1H-imidazol-1-yl)phenyl)-3-butenamide##STR111##

pale yellow oil.

NMR (CDCl₃) δ; 1.44˜1.68 (4H, m), 2.27 (3H, s), 2.32˜2.78 (6H, m), 3.14(2H, d, J=5.7 Hz), 3.15˜3.38 (2H, m), 3.84 (3H, s), 6.30 (1H, dt, J=5.7Hz, 15.8 Hz), 6.55 (1H, d, J=15.8 Hz), 6.56 (1H, br), 6.81 (1H, d, J=8.4Hz), 7.02 (1H, dd, J=2.2 Hz, 8.4 Hz), 7.12˜7.55 (7H, m), 7.82 (1H, s).

EXAMPLE 29(E)-N-[3-((N'-(2-(3,4-Dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl]-4-(4-(N²-methylureido)phenyl)-3-butenamide ##STR112##

pale yellow oil.

NMR (CDCl₃) δ; 1.40˜1.84 (2H, m), 2.20 (3H, s), 2.32˜2.84 (9H, m), 2.96(2H, d, J=6.2 Hz), 3.14˜3.28 (2H, m), 3.81 (3H, s), 3.83 (3H, s),5.75˜6.14 (2H, m), 6.31 (1H, d, J=15.8 Hz), 6.52˜6.81 (3H, m), 7.04 (2H,d, J=8.8 Hz), 7.23 (2H, d, J=8.8 Hz), 7.57 (1H, t, J=5 Hz), 8.06 (1H,s).

EXAMPLE 30(E)-N-[4-((N'-(2-(3,5-Dimethoxyphenyl)ethyl-N'-methyl)amino)butyl]-4-(4-(N.sup.2-methylureido)phenyl)-3-butenamide ##STR113##

white solid.

NMR (CDCl₃) δ; 1.40˜1.76 (4H, m), 2.12˜2.86 (12H, m), 2.96˜3.35 (4H, m),3.75 (6H, s), 5.76˜6.45 (6H, m), 6.78˜7.29 (5H, m), 7.92 (1H, s).

EXAMPLE 31(E)-N-[3-((N'-(2-(3,5-Dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl]-4-(4-(N²-methylthioureido)phenyl)-3-butenamide ##STR114##

white amorphous product.

NMR (CDCl₃) δ; 1.48˜1.85 (2H, m), 2.24 (3H, s), 2.38˜2.76 (6H, m), 2.99(2H, d, J=6.2 Hz), 3.09 (3H, d, J=4.4 Hz), 3.18˜3.45 (2H, m), 3.83 (6H,s), 5.83˜6.51 (3H, m), 6.55˜6.83 (3H, m), 7.06˜7.38 (5H, m), 8.32 (1H,br s).

EXAMPLE 32(E)-N-[3-((N'-(2-(3,4-Dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl]-4-[4((1-methylthio-2-nitroethen-1-yl)amino)phenyl]-3-butenamide ##STR115##

lightly orange-colored amorphous product.

NMR (CDCl₃) δ; 1.44˜1.80 (2H, m), 2.21 (3H, s), 2.30˜3.06 (11H, m),3.15˜3.20 (2H, m), 3.81 (3H, s), 3.82 (3H, s), 6.08 (1H, dt, J=6.2 Hz,15.8 Hz), 6.39 (1H, d, J=15.8 Hz), 6.40 (1H, br), 6.52˜6.80 (4H, m),7.05 (2H, d, J=8.6 Hz), 7.12˜7.36 (3H, m).

EXAMPLE 33(E)-N-[4-((N'-(2-Phenylethyl)-N'-methyl)amino)butyl]-4-(4-(1,4-dihydro-4-oxo-1-pyridyl)phenyl)-3-butenamide##STR116##

yellow oil.

NMR (CDCl₃) δ; 1.42˜1.68 (4H, m), 2.08˜2.93 (9H, m), 2.96˜3.39 (4H, m),6.07˜6.68 (4H, m), 6.89˜7.32 (8H, m), 7.36˜7.67 (4H, m).

EXAMPLE 34(E)-N-[4-((N'-(2-(4-Methoxy-3-methylphenyl)ethyl)-N'-methyl)amino)butyl]-4-(4-(1,4-dihydro-4-oxo-1-pyridyl)phenyl)-3-butenamide##STR117##

yellow oil.

NMR (CDCl₃) δ; 1.48˜1.70 (4H, m), 2.18 (3H, s), 2.26˜2.80 (9H, m),3.08˜3.40 (4H, m), 3.79 (3H, s), 6.15˜6.56 (4H, m), 6.64˜7.04 (4H, m),7.18˜7.34 (2H, m), 7.40˜7.65 (4H, m).

EXAMPLE 35(E)-N-[4-((N'-(2-(3-Chloro-4-methoxyphenyl)ethyl)-N'-methyl)amino)butyl]-4-(4-(1,4-dihydro-4-oxo-1-pyridyl)phenyl)-3-butenamide##STR118##

pale yellow oil.

NMR (CDCl₃) δ; 1.44˜1.68 (4H, m), 2.22˜2.88 (9H, m), 3.08˜3.39 (4H, m),3.86 (3H, s), 6.14˜6.72 (5H, m), 6.82 (1H, d, J=8.4 Hz), 7.04 (1H, dd,J=1.8 Hz, 8.4 Hz), 7.12˜7.26 (3H, m), 7.27˜7.66 (4H, m).

EXAMPLE 36 (E)-N-[4-((N'-(2-Phenylethyl)-N'-methyl)amino)butyl]-4-(4-(N³-methyl-N² -cyanoguanidino)phenyl)-3-butenamide ##STR119##

pale yellow oil.

NMR (CDCl₃) δ; 1.36˜1.70 (4H, m), 2.21˜2.96 (12H, m), 2.98˜3.35 (4H, m),5.59 (1H, br d, J=5 Hz), 6.15 (1H, dt, J=5.3 Hz, 15.8 Hz), 6.42 (1H, d,J=15.8 Hz), 6.76 (1H, t, J=5.3 Hz), 6.98˜7.38 (10H, m).

EXAMPLE 37(E)-N-[4-((N'-(2-(4-Methoxyphenyl)ethyl)-N'-methyl)amino)butyl]-4-(4-(N.sup.3-methyl-N² -cyanoguanidino)phenyl)-3-butenamide ##STR120##

pale yellow amorphous product.

NMR (CDCl₃) δ; 1.42˜1.70 (4H, m), 2.22˜2.92 (12H, m), 2.98˜3.34 (4H, m),3.75 (3H, s), 5.57 (1H, br d, J=6 Hz), 6.18 (1H, dt, J=5.7 Hz, 15.8 Hz),6.43 (1H, d, J=15.8 Hz), 6.65˜6.82 (3H, m), 6.99˜7.38 (7H, m).

EXAMPLE 38(E)-N-[4-((N'-(2-(3-Methoxyphenyl)ethyl)-N'-methyl)amino)butyl]-4-(4-(N.sup.3-methyl-N² -cyanoguanidino)phenyl)-3-butenamide ##STR121##

pale yellow amorphous product.

NMR (CDCl₃) δ; 1.36˜1.64 (4H, m), 2.16˜2.92 (12H, m), 2.98˜3.33 (4H, m),3.76 (3H, s), 5.02 (1H, br d, J=6 Hz), 6.14 (1H, dt, J=5.3 Hz, 15.8 Hz),6.42 (1H, d, J=15.8 Hz), 6.62˜6.91 (4H, m), 7.03˜7.36 (6H, m).

EXAMPLE 39(E)-N-[4-((N'-(2-(4-Chlorophenyl)ethyl)-N'-methyl)amino)butyl]-4-(4-(N.sup.3-methyl-N² -cyanoguanidino)phenyl)-3-butenamide ##STR122##

pale yellow amorphous product.

NMR (CDCl₃) δ; 1.38˜1.64 (4H, m), 2.15˜2.82 (11H, m), 2.98˜3.32 (4H, m),5.47 (1H, br d, J=6 Hz), 6.18 (1H, dt, J=5.7 Hz, 15.8 Hz), 6.45 (1H, d,J=15.8 Hz), 6.54 (1H, t, J=5.7 Hz), 6.98˜7.44 (9H, m).

EXAMPLE 40(E)-N-[4-((N'-(2-(3,4-Dichlorophenyl)ethyl)-N'-methyl)amino)butyl]-4-(4-(N.sup.3-methyl-N² -cyanoguanidino)phenyl)-3-butenamide ##STR123##

pale yellow amophour product.

NMR (CDCl₃) δ; 1.40˜1.62 (4H, m), 2.10˜2.76 (9H, m), 2.85 (3H, d, J=4.4Hz), 3.02˜3.36 (4H, m), 5.34 (1H, br d, J=6 Hz), 6.20 (1H, dt, J=6.2 Hz,16.0 Hz), 6.40 (1H, br), 6.46 (1H, d, J=16.0 Hz), 6.92˜7.42 (10H, m).

EXAMPLE 41(E)-N-[4-((N'-(2-(4-Methylphenyl)ethyl)-N'-methyl)amino)butyl]-4-(4-(N.sup.3-methyl-N² -cyanoguanidino)phenyl)-3-butenamide ##STR124##

yellow oil.

NMR (CDCl₃) δ; 1.39˜1.65 (4H, m), 2.04˜2.95 (15H, m), 2.98˜3.32 (4H, m),5.80 (1H, br d, J=5.8 Hz), 6.18 (1H, dt, J=5.7 Hz, 15.8 Hz), 6.43 (1H,d, J=15.8 Hz), 6.88˜7.40 (10H, m).

EXAMPLE 42(E)-N-[3-((N'-(2-(3,4-Dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl]-4-(4-(1,4-dihydro-4-oxopyrimidin-2-yl)phenyl)-3-butenamide##STR125##

white amorphous product.

NMR (CDCl₃) δ; 1.55˜1.86 (2H, m), 2.26 (3H, s), 2.42˜2.79 (6H, m), 2.96(2H, d, J=6.2 Hz), 3.22˜3.41 (4H, m), 3.81 (3H, s), 3.82 (3H, s), 5.85(1H, d, J=6.6 Hz), 6.07 (1H, dt, J=6.2 Hz, 15.8 Hz), 6.36 (1H, d, J=15.8Hz), 6.58˜6.84 (3H, m), 7.08˜7.28 (2H, m), 7.32˜7.72 (4H, m).

EXAMPLE 43(E)-N-[4-((N'-(2-(3,5-Dimethoxyphenyl)ethyl)-N'-methyl)amino)butyl]-4-(4-(1,4-dihydro-4-oxopyrimidin-2-yl)phenyl)-3-butenamide##STR126##

NMR (CDCl₃) δ; 1.35˜1.55 (4H, m), 2.24 (3H, s), 2.36 (2H, m), 2.54˜2.61(2H, m), 2.63˜2.71 (2H, m), 2.98 (2H, d, J=6.2 Hz), 3.13˜3.22 (2H, m),3.74 (6H, s), 5.74 (1H, d, J=6 Hz), 6.02 (1H, dt, J=6.2 Hz, 15.8 Hz),6.22˜6.39 (4H, m), 6.98 (1H, br), 7.09 (2H, d, J=8.4 Hz), 7.26 (1H, br),7.36 (2H, d, J=8.4 Hz), 7.57 (1H, d, J=8.6 Hz).

EXAMPLE 44(E)-N-[4-((N'-(2-(3,4-Dimethoxyphenyl)ethyl)-N'-methyl)amino)butyl]-4-(4-(1H-imidazol-1-yl)thiophen-2-yl)-3-butenamide##STR127##

yellow oil.

NMR (CDCl₃) δ; 1.4˜1.7 (4H, m), 2.31 (3H, s), 2.3˜2.8 (6H, m), 3.10 (2H,d, J=6.5 Hz), 3.2˜3.4 (2H, m), 3.83 (3H, s), 3.85 (3H, s), 6.14 (1H, dt,J=16.0 Hz, 6.5 Hz), 6.54 (1H, d, J=16.0 Hz), 6.7˜6.9 (3H, m), 6.97 (2H,bs), 7.12 (1H, bs), 7.19 (1H, bs), 7.5 (1H, m), 7.8 (1H, bs).

EXAMPLE 45(E)-N-[4-((N'-(2-(3,5-Dimethoxyphenyl)ethyl)-N'-methyl)amino)butyl]-4-(4-(1H-imidazolyl-1-yl)thiophen-2-yl)-3-butenamide##STR128##

NMR (CDCl₃) δ; 1.55˜1.50 (4H, m), 2.26 (3H, s), 2.37˜2.41 (2H, m),2.57˜2.61 (2H, m), 2.68˜2.72 (2H, m), 3.07 (2H, dd, J=7.0 Hz, 1.5 Hz),3.21˜3.26 (2H, m), 3.75 (6H, s), 6.23 (1H, dt, J=15.5 Hz, 7.0 Hz),6.29˜6.30 (1H, m), 6.32˜6.33 (2H, m), 6.55 (1H, dt, J=15.5 Hz), 1.5 Hz),6.56 (1H, m), 6.96 (2H, m), 7.13 (1H, m), 7.18 (1H, m), 7.76 (1H, m).

EXAMPLE 46(E)-N-[4-((N'-(2-(3,4-Dimethoxyphenyl)ethyl)-N'-methyl)amino)butyl]-4-(2-(1H-imidazol-1-yl)thiophen-5-yl)-3-butenamide##STR129##

yellow oil.

NMR (CDCl₃) δ; 1.5˜1.7 (4H, m), 2.31 (3H, s), 2.3˜2.6 (2H, m), 2.6˜2.8(4H, m), 3.08 (2H, d, J=7.0 Hz), 3.1˜3.5 (2H, m), 3.84 (3H, s), 3.86(3H, s), 6.11 (1H, dt, J=15.5 Hz, 7.0 Hz), 6.50 (1H, d, J=15.5 Hz), 6.6(1H, m), 6.7˜6.9 (5H, m), 7.15 (2H, m), 7.71 (1H, m).

EXAMPLE 47(E)-N-[4-((N'-(2-(3,4-Dimethoxyphenyl)ethyl)-N-methyl)amino)butyl]-4-(4-(4-pyridyl)phenyl)-3-butenamide##STR130##

pale yellow oil.

NMR (CDCl₃) δ; 1.4˜1.7 (4H, m), 2.28 (3H, s), 2.3˜2.9 (6H, m), 3.15 (2H,d, J=6.0 Hz), 3.2˜3.4 (2H, m), 3.83 (3H, s), 3.85 (3H, s), 6.3˜6.9 (6H,m), 7.3˜7.7 (6H, m), 8.5˜8.7 (2H, m).

EXAMPLE 48(E)-[N-(4-((N'-(2-(3,4-Dimethoxyphenyl)ethyl)-N'-methyl)amino)butyl]-4-(4-(3-pyridyl)phenyl)-3-butenamide##STR131##

pale yellow oil.

NMR (CDCl₃) δ; 1.5˜1.7 (4H, m), 2.35 (3H, s), 2.4˜2.6 (2H, m), 2.6˜2.9(4H, m), 3.16 (1H, d, J= 6.0 Hz), 3.2˜3.4 (2H, m), 3.83 (3H, s), 3.85(3H, s), 6.40 (1H, dt, J=16.0 Hz, 6.0 Hz), 6.50 (1H, d, J=16.0 Hz), 6.6(1H, m), 6.7˜6.9 (3H, m), 7.2˜7.6 (5H, m), 7.7˜7.9 (1H, m), 8.54 (1H,dd, J=5.0 Hz, 1.0 Hz), 8.8 (1H, m).

EXAMPLE 49(E)-[N-(4-((N'-(2-(3,5-Dimethoxyphenyl)ethyl)-N'-methyl)amino)butyl]-4-(4-(3-pyridyl)phenyl)-3-butenamide##STR132##

pale yellow oil.

NMR (CDCl₃) δ; 1.4˜1.7 (4H, m), 2.28 (3H, s), 2.3˜2.6 (2H, m), 2.6˜2.8(4H, m), 3.14 (2H, d, J=6 Hz), 3.16˜3.4 (2H, m), 3.76 (6H, s), 6.24˜6.52(6H, m), 7.28˜7.6 (5H, m), 7.76˜7.92 (1H, m), 8.56 (1H, dd, J=5 Hz, 1Hz), 8.82 (1H, d, J=1 Hz).

EXAMPLE 50(E)-N-[4-((N'-(2-(4-Nitrophenyl)ethyl)-N'-methyl)amino)butyl]-4-(4-(1H-imidazol-1-yl)phenyl)-3-butenamide##STR133##

lightly red oil.

NMR (CDCl₃) δ; 1.4˜1.7 (4H, m), 2.32 (3H, s), 2.3˜3.0 (6H, m), 3.1˜3.4(4H, m), 5.96˜6.2 (1H, broad), 6.2˜6.7 (2H, m), 7.16˜7.56 (8H, m), 7.84(1H, s), 8.08 (1H, s), 8.18 (1H, s).

EXAMPLE 51(E)-N-[4-((N'-(2-(3,4-Dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl]-4-[4-((1-methylimidzolin-4-on-2-yl)amino)phenyl]-3-butenamide##STR134##

yellow oil.

NMR (CDCl₃) δ; 1.50˜1.85 (2H, m), 2.10 (3H, s), 2.30˜2.80 (6H, m), 3.25(2H, d, J=4 Hz), 3.28 (3H, s), 3.76 (5H, s), 3.79 (3H, s), 5.96˜7.58(8H, m).

EXAMPLE 52(E)-N-[4-((N'-(2-(3,4-Dimethoxyphenyl)ethyl)-N'-methyl)amino)butyl]-4-[4-((imidazolin-4-on-2-yl)amino)phenyl]-3-butenamide##STR135##

white wax.

NMR (CDCl₃) δ; 1.48˜1.84 (2H, m), 2.11 (3H, s), 2.30˜2.79 (6H, m), 3.25(2H, d, J=4 Hz), 3.76 (5H, s), 3.79 (3H, s), 5.97˜7.58 (9H, m).

PRODUCTION EXAMPLE 36 5-(1H-Imidazol-1-yl)furfural ##STR136##

14.17 g of 5-bromofurfural and 6.62 g of imidazole were dissolved in 80ml of N-methylpyrrolidone. 13.43 g of anhydrous potassium carbonate wasadded to the solution and the solution was stirred at 100° C. in anitrogen atmosphere for 9 h.

After leaving the reaction mixture to cool, water was added thereto. Theproduct was extracted with ethyl acetate and washed with water and thenwith a saturated aqueous common salt solution.

After drying over anhydrous magnesium sulfate, the solvent was distilledoff under reduced pressure. The product was purified according to silicagel column chromatography (solvent: dichloromethane/methanol=30/1). Theresulting solid was washed with ether to give 1.21 g of the intendedcompound in the form of a light orange solid (yield: 9%).

NMR (CDCl₃, 400 MHz) δ; 6.38 (1H, J=3.6 Hz), 7.23 (1H, dd, J=0.8 Hz, 1.2Hz), 7.34 (1H, d, J=3.6 Hz), 7.41 (1H, dd, J=0.4 Hz, 1.2 Hz), 8.05 (1H,dd, J=0.4 Hz, 0.8 Hz), 9.60 (1H, s).

PRODUCTION EXAMPLE 375-(1H-Imidazol-1-yl)-3-methyl-2-thiophenecarboxaldehyde ##STR137##

26 g of 3-methyl-2-thiophenecarboxaldehyde was dissolved in 100 ml ofchloroform and the solution was stirred by cooling with ice 11 ml ofbromine was added dropwise thereto. The temperature was elevated to roomtemperature and the mixture was stirred overnight. About 1 l of ethylacetate was added thereto and the mixture was washed with water, thenwith a saturated aqueous sodium hydrogencarbonate solution and finallywith a saturated aqueous common salt solution. After drying overanhydrous magnesium sulfate, the solvent was distilled off under reducedpressure to give 46.8 g of 5-bromo-3-methyl-2-thiophenecarboxaldehyde inthe form of a dark brown solid, which was subjected to the subsequentreaction without purification.

46.8 g of 5-bromo-3-methyl-2-thiophenecarboxaldehyde, 93 g of imidazoleand 3 g of copper powder were suspended in 230 ml of water. Thesuspension was heated under reflux in a nitrogen stream for 12 h.Aqueous ammonia was added thereto and the product was extracted withchloroform thrice and dried over anhydrous magnesium sulfate. Then thesolvent was distilled off under reduced pressure. Ethyl acetate wasadded to the residue. After extraction with dilute hydrochloric acidthrice, the aqueous layer was made alkaline with aqueous ammonia. Theproduct was extracted with chloroform thrice and dried over anhydrousmagnesium sulfate. The solvent was distilled off under reduced pressure.The product was purified according to silica gel column chromatographyto give 15.9 g of the intended compound in the form of a dark brownsolid (yield: 36%).

NMR (CDCl₃, 400 MHz) δ; 2.60 (3H, s), 6.88 (1H, s), 7.21 (1H, m), 7.26(1H, t, J=1.5 Hz), 7.86 (1H, m), 10.02 (1H, s).

PRODUCTION EXAMPLE 38 5-Bromo-2-thiophenecarboxaldehyde dimethyl acetal##STR138##

50 g of 5-bromo-2-thiophenecarboxaldehyde was dissolved in 200 ml ofmethylene chloride. A suspension of 50 g of montmorillonite K-10 inabout 50 ml of trimethyl o-formate was added to the solution and thesolution was stirred at room temperature for about 30 min.Montmorillonite K-10 was filtered off and the methylene chloride layerwas washed with a saturated aqueous sodium hydrogencarbonate solutionand then with a saturated aqueous common salt solution. After dryingover anhydrous magnesium sulfate, the solvent was distilled off underreduced pressure.

The residue was distilled under reduced pressure to give 55.9 g of theintended compound in the form of a light yellow oil.

NMR (CDCl₃, 400 MHz) δ; 3.35 (6H, s), 5.54 (1H, s), 6.82 (1H, d, J=3.5Hz), 6.95 (1H, d, J=3.5 Hz).

PRODUCTION EXAMPLE 39 5-(3-Pyridyl)thiophene-2-carboxaldehyde ##STR139##

50 ml of anhydrous tetrahydrofuran and a catalytic amount of iodine wereadded to 3.3 g of magnesium in a nitrogen stream and the resultingsolution was stirred. 20 g of 5-bromo-2-thiophenecarboxaldehyde dimethylacetal was dissolved in 100 ml of anhydrous tetrahydrofuran and thesolution was slowly dropped into the mixture prepared as described aboveso that the temperature would be kept at 30° to 50° C.

The Grignard reagent thus prepared was added to a solution of 10 ml of3-bromopyridine and 1.0 g of bis(1,3-diphenylphosphinopropane)nickel(II) chloride in anhydrous tetrahydrofuran. The resulting solution wasstirred at room temperature for 30 min and then heated under reflux for2 h. Diluted hydrochloric acid was added to the solution to make itacidic and the solution was stirred at room temperature for 30 min.Ethyl acetate was added thereto and the product was extracted withdiluted hydrochloric acid twice. Concentrated aqueous ammonia was addedto the resultant aqueous layer to make it alkaline. After extractionwith methylene chloride thrice, the organic layer was dried overanhydrous magnesium sulfate and the solvent was distilled off underreduced pressure.

The residue was purified according to silica gel column chromatographyto give 7.4 g of the intended compound in the form of a dark brown solid(yield: 43%).

NMR (CDCl₃, 400 MHz) δ; 7.40 (1H, ddd, J=8.0 Hz, 5.0 Hz, <1.0 Hz), 7.47(1H, d, J=4.0 Hz), 7.79 (1H, d, J=4.0 Hz), 7.95 (1H, ddd, J=8.0 Hz, 1.5Hz, <1.0 Hz), 8.64 (1H, dd, J=5.0 Hz, 1.5 Hz), 8.96 (1H, dd, J=1.5 Hz,<1.0 Hz), 9.94 (1H, s).

4-(2-Methoxy-5-pyridyl)benzaldehyde ##STR140##

white acicular crystals (yield: 68%).

NMR (CDCl₃, 400 MHz) δ; 4.06 (3H, s), 6.77 (1H, d, J=8.0 Hz), 7.43 (1H,dd, J=7.5 Hz, <1.0 Hz), 7.67 (1H, dd, J=8.0 Hz, 7.5 Hz), 7.97 (2H, ddd,J=8.5 Hz, 2.0 Hz, 1.5 Hz), 8.22 (2H, ddd, J=8.5 Hz, 2.0 Hz, 1.5 Hz),10.07 (1H, s).

PRODUCTION EXAMPLE 40 (E)-4-((5-(1H-Imidazol-1-yl)furan-2-yl)-3-butenoicacid ##STR141##

1.21 g of 5-(1H-imidazol-1-yl)furfural and 3.05 g ofβ-carboxyethyltriphenylphosphonium chloride were added to 15 ml oftetrahydrofuran and the mixture was cooled to -60° C. 10 ml of asolution of 1.84 g of potassium tert-butoxide in tetrahydrofuran wasslowly dropped thereinto under stirring and then the temperature wasslowly elevated to room temperature. Two hours later, water was addedand the mixture was concentrated under reduced pressure. Water andactive carbon were added to the residue and the mixture was filtered.The aqueous layer was washed with ether. Concentrated hydrochloric acidwas added to the aqueous layer to adjust its pH to about 4 and aprecipitate thus formed was recovered by filtration. It was washed withwater, acetone and ether successively to give 0.96 g of the intendedcompound in the form of a light brown solid (yield: 59%).

NMR (DMSO-d₆, 400 MHz) δ; 3.20 (2H, d, J=7.2 Hz), 6.19 (1H, dt, J=7.2Hz, 15.6 Hz), 6.38 (1H, d, J=15.6 Hz), 6.51 (1H, d, J=3.6 Hz), 6.54 (1H,d, J=3.6 Hz), 7.11 (1H, dd, J=0.8 Hz, 1.6 Hz), 7.66 (1H, dd, J=1.2 Hz,1.6 Hz), 8.18 (1H, dd, J=0.8 Hz, 1.2 Hz).

The following compounds were produced in the same manner as thatdescribed above:

(E)-4-(5-(1H-imidazol-1-yl)-3-methylthiophen-2-yl)-3-butenoic acid##STR142##

light yellow solid.

NMR (DMSO-d₆, 400 MHz) δ; 2.19 (3H, s), 3.21 (2H, dd, J=7.0 Hz, 1.5 Hz),5.91 (1H, dt, J=15.0 Hz, 7.0 Hz), 6.72 (1H, dt, J=15.0 Hz, 1.5 Hz), 7.05(1H, s), 7.09 (1H, dd, J=1.5 Hz, <1.0 Hz), 7.58 (1H, dd, J=1.5 Hz, 1.5Hz), 8.05 (1H, dd, J=1.5 Hz, <1.0 Hz), and

(E)-4-(5-(3-pyridyl)thiophen-2-yl)-3-butenoic acid ##STR143##

dark brown solid (yield: 75%)

NMR (DMSO-d₆, 400 MHz) δ; 3.18 (2H, d, J=7.0 Hz), 8.09 (1H, dt, J=16.0Hz, 7.0 Hz), 6.67 (1H, d, J=16.0 Hz), 7.08 (1H, d, J=4.0 Hz), 7.42 (1H,ddd, J=8.0 Hz, 4.5 Hz, <1.0 Hz), 7.53 (1H, d, J=4.0 Hz), 8.01 (1H, ddd,J=8.0 Hz, 2.0 Hz, <1.0 Hz), 8.47 (1H, dd, J=5.0 Hz, 1.5 Hz), 8.86 (1H,d, J=2.0 Hz).

PRODUCTION EXAMPLE 415-(1,4-Dihydro-4-oxo-1-pyridyl)thiophene-2-carboxaldehyde ##STR144##

25.0 g of 4-hydroxypyridine was suspended in 440 ml ofN,N-dimethylformamide. 11.04 g of sodium hydride (60% suspension inmineral oil) was added to the suspension in portions and the-suspensionwas stirred for 1 h. 32.8 ml of 5-bromothiophene-2-carboxaldehyde wasadded thereto and a reaction was conducted at 120° C. for 4 h.

The reaction mixture was left to cool and concentrated under reducedpressure. Water was added thereto and an insoluble matter was filteredoff. The product was washed with water, acetone and ether successivelyto give 26.86 g of the intended compound in the form of a light yellowpowder (yield: 50%).

NMR (CDCl₃, 400 MHz) δ; 6.50 (2H, m), 7.08 (1H, d, J=4.4 Hz), 7.65 (2H,m), 7.70 (1H, d, J=4.4 Hz), 9.88 (1H, s).

PRODUCTION EXAMPLE 42(E)-4-((5-(1,4-Dihydro-4-oxo-1-pyridyl)thiophen-2-yl)-3-butenoic acid##STR145##

26 86 g of 5-(1,4-dihydro-4-oxo-1-pyridyl)thiophene-2-carboxaldehyde and51.01 g of β-carboxyethyltriphenylphosphonium chloride were suspended in250 ml of tetrahydrofuran and the suspension was cooled to -50° C. 200ml of a solution of 30.88 g of potassium tert-butoxide intetrahydrofuran was slowly dropped thereinto. After the completion ofthe addition, the temperature was slowly elevated to room temperature.

Two hours after, water was added thereto and the aqueous layer waswashed with ether. Concentrated hydrochloric acid was added thereto toadjust the pH to 3. The product was extracted with chloroform/methanol(3/1) and dried over anhydrous magnesium sulfate. The solvent wasdistilled off under reduced pressure.

600 ml of methanol and 3 ml of concentrated sulfuric acid were added tothe residue and heated under reflux for 4 h. The mixture wasconcentrated under reduced pressure and an aqueous potassium carbonatesolution was added thereto. The product was extracted with ethylacetate, washed with water and a saturated aqueous common salt solutionand dried over anhydrous magnesium sulfate. The solvent was distilledoff.

The product was purified according to silica gel column chromatography(solvent: dichloromethane/methanol=50/1) to give 9.12 g of methyl esterof the intended compound in the form of a dark pink solid (yield: 25%).

NMR (CDCl₃, 400 MHz) δ; 3.25 (2H, d, J=7.2 Hz), 3.73 (3H, s), 6.13 (1H,dt, J=7.2 Hz, 15.6 Hz), 6.44 (2H, m), 6.54 (1H, d, J=15.6 Hz), 6.80 (1H,d, J=3.6 Hz), 6.84 (1H, d, J=3.6 Hz), 7.55 (2H, m).

8.49 g of the methyl ester thus produced was dissolved in 60 ml ofmethanol. 34 ml of a 1N-aqueous sodium hydroxide solution was addedthereto and stirred at room temperature for 8 h. The reaction mixturewas concentrated under reduced pressure. Water was added thereto and theaqueous layer was washed with ether. The pH of the solution was adjustedto 2 with concentrated hydrochloric acid and a precipitate thus formedwas recovered by filtration. It was washed with water and dried to give7.48 g of the intended compound in the form of a light orange yellowpowder (yield: 93%).

NMR (DMSO-d₆, 400 MHz) δ; 3.20 (2H, d, J=7.2 Hz), 6.05 (1H, dt, J=7.2Hz, 15.6 Hz), 6.22 (2H, m), 6.65 (1, d, J=15.6 Hz), 6.99 (1H, d, J=4Hz), 7.17 (1H, d, J=4 Hz), 7.96 (2H, m).

PRODUCTION EXAMPLE 43 Ethyl(E)-4-(4-(N-oxy-4-pyridyl)phenyl)-3-butenoate ##STR146##

0.70 g of (E)-4-(4-pyridylphenyl)-3-butenoic acid was suspended in 30 mlof ethanol. About 0.5 ml of concentrated sulfuric acid was added theretoand the resulting solution was heated under reflux for 1 h. Ethanol wasdistilled off under reduced pressure and ethyl acetate was added to theresidue. After washing with diluted aqueous ammonia, water and asaturated aqueous common salt solution successively followed by dryingover anhydrous magnesium sulfate, the solvent was distilled off underreduced pressure to give 0.70 g of the crude ethyl ester in the form ofa light yellow oil, which was then subjected to the subsequent reactionwithout purification.

0.70 g of the crude ethyl ester was dissolved in 100 ml of methylenechloride. 0.64 g of m-chloroperbenzoic acid was added thereto andstirred overnight. Ethyl acetate was added thereto and the reactionmixture was washed with an aqueous sodium hydrogensulfite solution and asaturated aqueous common salt solution. After drying over anhydrousmagnesium sulfate, the solvent was distilled off under reduced pressure.The product was purified according to silica gel column chromatographyto give 0.67 g of the intended compound in the form of a light yellowoil (yield: 63%).

NMR (CDCl₃, 400 MHz), δ; 1.30 (3H, t, J=7.0 Hz), 3.28 (2H, dd, J=7.0 Hz,<1.0 Hz), 4.19 (2H, q, J=7.0 Hz), 6.40 (1H, dt, J=16.0 Hz, 7.0 Hz), 6.50(1H, d, J=16.0 Hz), 7.5˜7.6 (6H, m), 8.25 (2H, m).

The following compound was obtained in the same manner as that describedabove:

Ethyl (E)-4-(4-(N-oxy-3-pyridyl)phenyl)-3-butenoate ##STR147##

white solid.

NMR (CDCl₃, 400 MHz), δ; 1.30 (3H, t, J=7.0 Hz), 3.28 (2H, dd, J=7.5 Hz,1.0 Hz), 4.20 (2H, q, J=7.0 Hz), 6.41 (1H, dt, J=16.0 Hz, 7.5 Hz), 6.53(1H, dt, J=7.5 Hz, 1.0 Hz), 7.31˜7.37 (1H, m), 7.4˜7.56 (5H, m),8.18˜8.20 (1H, m), 8.47˜8.49 (1H, m).

PRODUCTION EXAMPLE 44 Methyl (E)-4-(4-(N²-ethylthioureido)phenyl)-3-butenoate ##STR148##

2.00 g of methyl (E)-4-(4-aminophenyl)-3-butenoate was dissolved in 20ml of dioxane. 1.1 ml of ethyl isothiocyanate was added to the solutionand a reaction was conducted at 100° C. for 10 h. The solvent wasdistilled off and benzene was added to the residue. An insoluble matterwas filtered off and the residue was concentrated again.

The product was purified according to silica gel column chromatography(solvent: n-hexane/ethyl acetate=2/1) to give 1.65 g of the intendedcompound in the form of a light yellow solid (yield: 57%).

m.p. (° C.): 88 to 89 (recrystallized from n-hexane/ethyl acetate).

    ______________________________________                                        EMA for C.sub.14 H.sub.18 N.sub.2 O.sub.2 S:                                            C    H          N      S                                            ______________________________________                                        calcd (%)   60.41  6.52       10.06                                                                              11.52                                      found (%)   60.45  6.48       10.03                                                                              11.57                                      ______________________________________                                    

NMR (CDCl₃, 400 MHz) δ; 1.19 (3H, t, J=7.2 Hz), 3.27 (2H, d, J=6.8 Hz),3.67 (2H, m), 3.73 (3H, s), 5.95 (1H, br), 6.31 (1H, dt, J=6.8 Hz, 16Hz), 6.48 (1H, d, J=16 Hz), 7.14 (2H, d, J=8.4 Hz), 7.42 (2H, d, J=8.4Hz), 7.64 (1H, br s).

The following compound was produced in the same manner as that describedabove:

Methyl (E)-4-(4-(N² -n-propylthioureido)phenyl)-3-butenoate ##STR149##

light yellow solid (yield: 69%).

m.p. (°C.): 76.5 to 78 (recrystallized from n-hexane/ethyl acetate).

    ______________________________________                                        EMA for C.sub.15 H.sub.20 N.sub.2 O.sub.2 S:                                            C    H          N      S                                            ______________________________________                                        calcd (%)   61.61  6.89       9.58 10.97                                      found (%)   61.66  6.80       9.67 10.86                                      ______________________________________                                    

NMR (CDCl₃, 400 MHz), δ; 0.92 (3H, t, J=7.2 Hz), 1.60 (2H, sextet, J=7.2Hz), 3.27 (2H, d, J=6.8 Hz), 3.60 (2H, q, J=7.2 Hz), 3.73 (3H, s), 6.00(1H, br), 6.32 (1H, dt, J=6.8 Hz, 15.6 Hz), 6.48 (1H, d, J=15.6 Hz),7.14 (2H, d, J=8.4 Hz), 7.43 (2H, d, J=8.4 Hz), 7.61 (1H, s).

PRODUCTION EXAMPLE 45 Methyl (E)-4-(4-N²-isopropylthioureido)phenyl)-3-butenoate ##STR150##

2.00 g of (E)-4-(4-aminophenyl)-3-butenoate and 3.21 ml of triethylaminewere dissolved in 35 ml of chloroform and the solution was stirred undercooling with ice. 0.88 ml of thiophosgene was dropped thereinto and themixture was heated under reflux for 30 min. The reaction mixture wascooled again with ice. 0.98 ml of isopropylamine was dropped thereintoand the mixture was heated under reflux for 30 min. After leaving tocool, 1N hydrochloric acid was added thereto. The product was extractedwith chloroform and dried over anhydrous magnesium sulfate. The solventwas distilled off. The product was purified according to silica gelcolumn chromatography (solvent: n-hexane/ethyl acetate=3/1) to give 1.75g of the intended compound in the form of a yellow powder (yield: 57%).

m.p. (° C.): 123 to 124.5 (recrystallized from n-hexane/ethyl acetate).

    ______________________________________                                        EMA for C.sub.15 H.sub.20 N.sub.2 O.sub.2 S:                                            C    H          N      S                                            ______________________________________                                        calcd (%)   61.61  6.89       9.58 10.97                                      found (%)   61.53  6.83       9.60 10.95                                      ______________________________________                                    

NMR (CDCl₃, 400 MHz) δ; 1.21 (6H, d, J=6.4 Hz), 3.27 (2H, d, J=7.2 Hz),3.73 (3H, s), 4.58 (1H, m), 5.79 (1H, d, J=8.8 Hz), 6.32 (1H, dt, J=7.2Hz, 15.6 Hz), 6.49 (1H, d, J=15.6 Hz), 7.13 (2H, d, J=8.4 Hz), 7.42 (2H,d, J=8.4 Hz), 7.68 (1H, s).

PRODUCTION EXAMPLE 46 Methyl (E)-4-(4-(N³ -ethyl-N²-cyanoguanidino)phenyl)-3-butenoate ##STR151##

1.45 g of methyl (E)-4-(4-(N² -ethylthioureido)phenyl)-3-butenoate wasdissolved in 10 ml of 1,4-dioxane. 1.61 g ofN,N-dicyclohexylcarbodiimide, 0.33 g of cyanamide and a catalytic amountof diisopropylethylamine were added to the solution and stirred at 100°C. for 2 h. The reaction mixture was concentrated and purified accordingto silica gel column chromatography (solvent: n-hexane/ethylacetate=2/3) to give 1.40 g of the intended compound in the form of awhite powder (yield: 94%).

m.p. (° C.): 134 to 135.5 (recrystallized from n-hexane/ethyl acetate).

    ______________________________________                                        EMA for C.sub.15 H.sub.18 N.sub.4 O.sub.2 :                                            C          H      N                                                  ______________________________________                                        calcd (%)  62.92        6.34   19.57                                          found (%)  62.63        6.33   19.25                                          ______________________________________                                    

NMR (CDCl₃, 400 MHz) δ; 1.14 (3H, t, J=7.2 Hz), 3.28 (2H, d, J=7.2 Hz),3.33 (2H, dq, J=5.6 Hz, 7.2 Hz), 4.79 (1H, br), 6.33 (1H, dt, J=7.2 Hz,16 Hz), 6.49 (1H, d, J=16 Hz), 7.15 (1H, br s), 7.17 (2H, d, J=8.4 Hz),7.43 (2H, d, J=8.4 Hz).

The following compounds were produced in the same manner as thatdescribed above:

Methyl (E)-4-(4-(N³ -n-propyl-N² -cyanoguanidino)phenyl)-3-butenoate##STR152##

faint yellow solid (yield: 60%).

m.p. (° C.): 105.5 to 107 (recrystallized from n-hexane/ethyl acetate).

    ______________________________________                                        EMA for C.sub.16 H.sub.20 N.sub.4 O.sub.2 :                                            C          H      N                                                  ______________________________________                                        calcd (%)  63.98        6.71   18.65                                          found (%)  63.89        6.64   18.49                                          ______________________________________                                    

NMR (CDCl₃, 400 MHz) δ; 0.89 (3H, t, J=7.6 Hz), 1.53 (2H, sextet, J=7.6Hz), 3.24 (2H, dt, J=6.4, 7.6 Hz), 3.28 (2H, d, J=7.2 Hz), 3.73 (3H, s),4.84 (1H, br), 6.32 (1H, dt, J=7.6, 15.6 Hz), 6.49 (1H, d, J=15.6 Hz),7.17 (2H,d,J=8.4 Hz), 7.27 (1H, brs), 7.46 (2H, d, J=8.4 Hz), and

Methyl (E)-4-(4-(N³ -isopropyl-N² -cyanoguanidino)phenyl)-3-butenoate##STR153##

yellow solid (yield: 72%).

m.p. (° C.): 136 to 138.5 (recrystallized from n-hexane/ethyl acetate).

    ______________________________________                                        EMA for C.sub.16 H.sub.20 N.sub.4 O.sub.2 :                                            C          H      N                                                  ______________________________________                                        calcd (%)  63.98        6.71   18.65                                          found (%)  64.07        6.76   18.36                                          ______________________________________                                    

NMR (CDCl₃, 400 MHz) δ; 1.15 (6H, d, J=6.4 Hz), 3.28 (2H, d, J=7.2 Hz),3.73 (3H, s), 4.04 (1H, m), 4.59 (1H, d like, J=8 Hz), 6.33 (1H, dt,J=7.2, 16 Hz), 6.49 (1H, d, J=16 Hz), 7.14 (2H, d, J=8.4 Hz), 7.22 (1H,brs), 7.43 (2H, d, J=8.4 Hz).

PRODUCTION EXAMPLE 47 (E)-4-(4-(N³ -Ethyl-N²-cyanoguanidino)phenyl)-3-butenoic acid ##STR154##

1.20 g of methyl (E)-4-(4-(N³ -ethyl-N²-cyanoguanidino)phenyl)-3-butenoate was dissolved in 10 ml of methanol.9.2 ml of a 1N aqueous sodium hydroxide solution was added to thesolution and stirred at room temperature for 8 h. The reaction mixturewas filtered. Concentrated hydrochloric acid was added to the filtrateto adjust its pH to 2. A precipitate thus formed was recovered byfiltration and washed with water to give 0.86 g of the intended compoundin the form of a faint yellow powder (yield: 75%).

m.p. (° C.): 159 to 161 (dec.) (recrystallized from n-hexane/ethylacetate).

    ______________________________________                                        EMA for C.sub.14 H.sub.16 N.sub.4 O.sub.2 :                                            C          H      N                                                  ______________________________________                                        calcd (%)  61.75        5.92   20.58                                          found (%)  61.63        5.95   20.56                                          ______________________________________                                    

NMR (DHSO-d₆, 400 MHz) δ; 1.08 (3H, t, J=7.2 Hz), 3.18 (2H, d, J=6.8Hz), 3.24 (1H, m), 4.56 (1H, t, J=5.6 Hz), 6.25 (1H, dt, J=6.8, 16 Hz),6.46 (1H, d, J=16 Hz), 7.19 (2H, d, J=8.8 Hz), 7.38 (2H, d, J=8.8 Hz),8.92 (1H, s).

The following compounds were produced in the same manner as thatdescribed above:

(E)-4-(4-(N³ -n-Propyl-N² -cyanoguanidino)phenyl)-3-butenoic acid##STR155##

faint yellow powder (yield: 83%).

m.p. (° C.): 156.5 to 158 (dec.) (recrystallized from n-hexane/ethylacetate).

    ______________________________________                                        EMA for C.sub.15 H.sub.18 N.sub.4 O.sub.2 :                                            C          H      N                                                  ______________________________________                                        calcd (%)  62.92        6.34   19.57                                          found (%)  62.81        6.34   19.38                                          ______________________________________                                    

NMR (DHSO-d₆, 400 MHz) δ; 0.86 (3H, t, J=7.2 Hz), 1.51 (2H, sextet,J=7.2 Hz), 3.16 (1H, m), 3.18 (2H, d, J=7.2 Hz), 6.25 (1H, dt, J=7.2,15.6 Hz), 6.46 (1H, d, J=15.6 Hz), 7.19 (2H, d, J=8.4 Hz), 7.21 (1H, t,J=5.6 Hz), 7.38 (2H, d, J=8.4 Hz), 8.93 (1H, s).

(E)-4-(4-(N³ -Isopropyl-N² -cyanoguanidino)phenyl)-3 butenoic acid##STR156##

faint yellow powder (yield: 88%)

m.p. (° C.): 155 to 158 (dec.) (recrystallized from n-hexane/ethylacetate).

    ______________________________________                                        EMA for C.sub.15 H.sub.18 N.sub.4 O.sub.2 :                                            C          H      N                                                  ______________________________________                                        calcd (%)  62.92        6.34   19.57                                          found (%)  62.81        6.34   19.38                                          ______________________________________                                    

NMR (DMSO-d₆, 400 MHz) δ; 1.13 (6H, d, J=6.8 Hz), 3.17 (2H, d, J=7.2Hz), 3.99 (1H, m), 6.24 (1H, dt, J=7.2, 16 Hz), 6.45 (1H, d,-J=16 Hz),7.02 (1H, d, J=8.4 Hz), 7.16 (2H, d, J=8.8 Hz), 7.37 (2H, d, J=8.8 Hz),8.94 (1H, s).

(E)-4-(4-(N-Oxy-3-pyridyl)phenyl)-3-butenoic acid ##STR157##

light yellow powder (yield: 75%).

NMR (DMSO-d₆, 400 MHz) δ; 3.23 (2H, dd, J=7.0, <1.0 Hz), 6.42 (1H, dt,J=16.0, 7.0 Hz), 6.56 (1H, dt, J=7.0, <1.0 Hz), 7.49 (1H, ddd, J=8.0,7.0, <1.0 Hz), 7.54 (2H, d, J=8.0 Hz), 7.67 (1H, ddd, J=8.0, 1.5, <1.0Hz), 7.72 (2H, d, J=8.0 Hz), 8.20 (1H, ddd, J=6.5, 1.0, <1.0 Hz), 8.59(1H, dd, J=1.5, <1.0 Hz).

(E)-4-(4-(2-Methoxy-5-pyridyl)phenyl)-3-butenoic acid ##STR158##

light yellow platy crystals.

NMR (DMSO-d₆, 400 MHz) δ; 3.23 (2H, dd, J=7.0, 1.0 Hz), 3.96 (3H, s),6.40 (1H, dt, J=16.0, 7.0 Hz), 6.56 (1H, dt, J=16.0, 1.0 Hz), 6.76 (1H,d, J=8.5 Hz), 7.52 (2H, d, J=8.5 Hz), 7.56 (1H, d, J=7.5 Hz), 7.77 (1H,dd, J=8.5, 7.5 Hz), 8.07 (2H, d, J=8.5 Hz).

PRODUCTION EXAMPLE 483-((2-(3,4-Dimethoxyphenyl)ethyl)amino)butyronitrile ##STR159##

A mixture of 10.0 g of 2-(3,4-dimethoxyphenyl)ethylamine with 14 ml ofcrotononitrile was stirred at 100° C. for 30 h.

The mixture was concentrated under reduced pressure and the product waspurified according to silica gel column chromatography (solvent: ethylacetate) to give 7.57 g of the intended compound in the form of a lightbrown oil (yield: 55%).

NMR (CDCl₃, 400 MHz) δ; 1.22 (3H, d, J=6.4 Hz), 1.38 (1H, br), 2.43 (2H,d, J=5.6 Hz), 2.70-2.80 (2H, m), 2.81-2.92 (2H, m), 3.04 (1H, m), 3.87(3H, s), 3.88 (3H, s), 6.74 (1H, d, J=2 Hz), 6.75 (1H, dd, J=2, 8 Hz),6.81 (1H, d, J=8 Hz).

PRODUCTION EXAMPLE 493-(N-(2-(3,4-Dimethoxyphenyl)ethyl-N-methyl)amino)butyronitrile##STR160##

A mixture of 20.0 g of N-methyl-N-(2-(3,4-dimethoxyphenyl)ethylaminewith 50 ml of crotononitrile was heated under reflux for 30 h.

The mixture was concentrated under reduced pressure and the product waspurified according to silica gel chromatography (solvent: n-hexane/ethylacetate=3/2) to give 9.49 g of the intended compound in the form of ayellow solid (yield: 35%).

NMR (CDCl₃, 400 MHz) δ; 1.17 (3H, d, J=6.8 Hz), 2.30 (1H, dd, J=7.6,16.8 Hz), 2.31 (3H, s), 2.47 (1H, dd, J=6, 16.8 Hz), 2.56-2.74 (4H, m),3.15 (1H, m), 3.86 (3H, s), 3.88 (3H, s), 6.73 (1H, d, J=2 Hz), 6.74(1H, dd, J=2, 8.4 Hz), 6.80 (1H, d, J=8.4 Hz).

PRODUCTION EXAMPLE 50 3-((2-(3,4-Dimethoxyphenyl)ethyl)amino)butylamine##STR161##

7.57 g of 3-((2-(3,4-dimethoxyphenyl)ethyl)amino)butyronitrile wasdissolved in 60 ml of a solvent. 0.5 g of platinum oxide and 5 ml ofconcentrated hydrochloric acid were added to the solution andhydrogenation was conducted at room temperature under 3 kg/cm² for 4 h.The catalyst was filtered off and the product was thoroughly washed withmethanol and concentrated under reduced pressure. Dilute aqueous ammoniawas added thereto. After extraction with chloroform followed by dryingover anhydrous potassium carbonate, the solvent was distilled off. Afterdistillation under reduced pressure, 5.23 g of the intended compound wasobtained in the form of a colorless oil (yield: 68%).

bp (° C.); 154˜159 (˜1 mmHg).

NMR (CDCl₃, 400 MHz) δ; 1.05 (3H, d, J=6 Hz), 1.1-1.4 (3H, br), 1.45(1H, m), 1.55 (1H, m), 2.65-2.85 (6H, m), 2.91 (1H, m), 3.86 (3H, s),3.87 (3H, s), 6.74 (1H, d, J=2 Hz), 6.75 (1H, dd, J=2, 8.8 Hz), 6.81(1H, d, J=8.8 Hz).

The following compound was produced in the same manner as that describedabove:

3-(N-((2-(3,4-dimethoxyphenyl)ethyl)-N-methyl)amino)butylamine##STR162##

colorless oil.

b.p. (° C.); 151˜155 (˜1 mmHg).

NMR (CDCl₃, 90 MHz) δ; 0.93 (3H, d, J=6.3 Hz), 0.93-1.82 (4H, m), 2.12(3H, s), 2.24-2.93 (7H, m), 3.78 (3H, s), 3.83 (3H, s), 6.54-6.84 (3H,m).

EXAMPLE 53(E)-[N-(3-(N'-(2-(3,4-Dimethoxyphenyl)ethyl)-N'-methyl)amino)butyl]-4-[5-(1H-imidazol-1-yl)thiophen-2-yl]-3-butenamide##STR163##

0.59 g of (E)-4-(5-(1H-imidazol-1-yl)thiophen-2-yl)-3-butenoic acid,0.74 g of3-((N-(2-(3,4-dimethoxyphenyl)ethyl)-N-methyl)amino)butylamine, 0.57 gof N,N'-dicyclohexylcarbodiimide and 0.37 g of N-hydroxybenzotriazolewere added to 9 ml of 50% hydrous acetonitrile and stirred at 70° C. for30 min. A precipitate thus formed was filtered off and the filtrate wasconcentrated under reduced pressure. The product was purified accordingto silica gel column chromatography (solvent:dichloromethane/methanol/concentrated aqueous ammonia=1000/100/3) togive 1.18 g of the intended compound in the form of a yellow oil.(Yield: 98%).

NMR (CDCl₃, 400 MHz) δ; 0.95 (3H, d, J=6.8 Hz), 1.49 (1H, m), 1.05 (1H,m), 2.23 (3H, s), 2.56˜2.78 (4H, m), 2.87 (1H, m), 2.97 (2H, d, J=7.2Hz), 3.13 (1H, m), 3.52 (1H, m), 3.84 (3H, s), 3.86 (3H, s), 6.04 (1H,dt, J=7.2 Hz, 15.6 Hz), 6.51 (1H, d, J=15.6 Hz), 6.62˜6.71 (2H, m), 6.75(1H, d, J=3.6 Hz), 6.77 (1H, d, J=8.8 Hz), 6.80 (1H, d, J=3.6 Hz), 7.12(1H, t, J=1.2 Hz), 7.15 (1H, t, J=1.2 Hz), 7.25 (1H, br), 7.70 (1H, t,J=1.2 Hz).

EXAMPLE 54(E)-[N-(3-(N'-(2-(3,4-Dimethoxyphenyl)ethyl)amino))butyl]-4-[5-(1H-imidazol-1-yl)thiophen-2-yl]-3-butenamide##STR164##

0.59 g of (E)-4-(5-(1H-imidazol-1-yl)thiopen-2-yl)-3-butenoic acid, 0.69g of 3-((2-(3,4-dimethoxyphenyl)ethyl)amino)butylamine, 0.57 g ofN,N'-dicyclohexylcarbodiimide and 0.37 g of N-hydroxybenzotriazole wereadded to 8 ml of 50% hydrous acetonitrile and stirred at 70° C. for 30min. A precipitate thus formed was filtered off and the filtrate wasconcentrated under reduced pressure. An aqueous potassium carbonatesolution was added to the residue. After extraction with chloroformfollowed by drying over anhydrous potassium carbonate, the solvent wasdistilled out. The product was purified according to silica gel columnchromatography (solvent: dichloromethane/methanol/concentrated aqueousammonia=1000/100/3) to give 1.12 g of the intended compound in the formof a yellow oil.

(Yield: 96%)

NMR (CDCl₃, 400 MHz) δ; 1.11 (3H, d, J=6.4 Hz), 1.55 (1H, m), 1.62˜1.90(2H, m), 2.64˜2.88 (4H, m), 2.94 (1H, m), 3.02 (2H, dd, J=1.2 Hz, 7.2Hz), 3.30 (1H, m), 3.43 (1H, m), 3.84 (3H, s), 3.86 (3H, s), 6.07 (1H,dt, J=7.2 Hz, 15.6 Hz), 6.54 (1H, dt, J=1.2 Hz, 15.6 Hz), 6.66˜6.72 (2H,m), 6.77 (1H, d, J=7.2 Hz), 6.78 (1H, d, J=3.6 Hz), 6.82 (1H, d, J=3.6Hz), 7.13 (1H, t, J=1.2 Hz), 7.15 (1H, d, J=1.2 Hz), 7.29 (1H, br), 7.72(1H, d, J=1.2 Hz).

EXAMPLE 55(E)-[N-(4-(N'-(2-(3,5-Dimethoxyphenyl)ethyl)-N'-methyl)amino)butyl]-4-[5-(1,4-dihydro-4-oxo-1-pyridyl)thiophen-2-yl]-3-butenamide##STR165##

0.65 g of(E)-4-(5-(1,4-dihydro-4-oxo-1-pyridyl)thiophen-2-yl)-3-butenoic acid,0.73 g of N-methyl-N-(2-(3,5-dimethoxyphenyl)ethyl)-1,4-diaminobutane,0.57 g of N,N'-dicyclohexylcarbodiimide and 0.37 g ofN-hydroxybenzotriazole were added to 8 ml of 50% hydrous acetonitrileand stirred at 70° C. for 30 min. A precipitate thus formed was filteredoff, an aqueous potassium carbonate solution was added to the filtrateand the product was extracted with chloroform. The extract was driedover anhydrous potassium carbonate and the solvent was distilled offunder reduced pressure. The product was purified according to silica gelcolumn chromatography (solvent: dichloromethane/methanol/concentratedaqueous ammonia=1000/100/3) to give 1.15 g of the intended compound inthe form of a light brown oil. (Yield: 90%).

NMR (CDCl₃, 400 MHz) δ; 1.58˜1.62 (4H, m), 2.30 (3H, s), 2.38˜2.42 (2H,m), 2.58˜2.66 (2H, m), 2.68˜2.74 (2H, m), 3.08 (2H, dd, J=1.2 Hz, 7.2Hz), 3.21˜3.29 (2H, m), 3.77 (6H, s), 6.14 (1H, dt, J=7.2 Hz, 15.6 Hz),6.31 (1H, t, J=2 Hz), 6.34 (2H, d, J=2 Hz), 6.44 (2H, m), 6.51 (1H, br),6.54 (1H, dt, J=1.2 Hz, 15.6 Hz), 6.78 (1H, d, J=3.6 Hz), 6.82 (1H, d,J=3.6 Hz), 7.53 (2H, m).

EXAMPLE 56(E)-[N-(4-(2-(3,5-Dimethoxyphenyl)ethyl)-N'-methyl)amino)butyl]-4-[5-(1H-imidazol-1-yl)furan-2-yl]-3-butenamide##STR166##

0.55 g of (E)-4-(5-(1H-imidazol-1-yl)furan-2-yl)-3-butenoic acid, 0.69 gof N-methyl-N-(2-(3,5-dimethoxyphenyl)ethyl)-1,4-diaminobutane, 0.57 gof N,N'-dicyclohexylcarbodiimide and 0.37 g of N-hydroxybenzotriazolewere added to 8 ml of 50% hydrous acetonitrile and stirred at 70° C. for30 min. A precipitate thus formed was filtered off and the filtrate wasconcentrated under reduced pressure. An aqueous potassium carbonatesolution was added to the residue and the product was extracted withchloroform. The extract was dried over anhydrous potassium carbonate andthe solvent was distilled off. The product was purified according tosilica gel column chromatography (solvent:dichloromethane/methanol/concentrated aqueous ammonia=1000/100/3) togive 0.9 g of the intended compound in the form of a yellow oil. (Yield:77%).

NMR (CDCl₃, 400 MHz) δ; 1.50˜1.58 (4H, m), 2.28 (3H, s), 2.41 (2H, m),2.57˜2.64 (2H, m), 2.67˜2.74 (2H, m), 3.09 (2H, d, J=6.4 Hz), 3.22˜3.28(2H, m), 3.77 (6H, s), 6.14 (1H, d, J=3.6 Hz), 6.23 (1H, dt, J=6.4 Hz,15.6 Hz), 6.27 (1H, d, J=3.6 Hz), 6.31 (1H, t, J=2.4 Hz), 6.34 (2H, d,J=2.4 Hz), 6.36 (1H, br), 7.16 (1H, t, J=1.2 Hz), 7.25 (1H, t, J=1.2Hz), 7.85 (1H, t, J=1.2 Hz).

EXAMPLE 57(E)-[N-(4-(N'-(2-(3,4-Dimethoxyphenyl)ethyl)-N'-methyl)amino)butyl]-4-[4-(N-oxy-4-pyridyl)phenyl]-3-butenamide ##STR167##

0.67 g of ethyl (E)-4-(4-(N-oxy-4-pyridyl)phenyl)-3-butenoate wasdissolved in 50 ml of methanol. 1.0 g of potassium hydroxide was addedto the solution and stirred overnight. The solvent was distilled offunder reduced pressure. Water was added to the residue and an insolublematter thus formed was filtered off. Diluted hydrochloric acid was addedto the aqueous layer to adjust its pH to 4 to 5. Crystals thus formedwere recovered by filtration and dried under reduced pressure to give0.47 g of a crude carboxylic acid in the form of orange yellow crystals.This product was subjected to the subsequent reaction withoutpurification.

0.47 g of the crude carboxylic acid, 0.42 g ofN,N'-dicyclohexylcarbodiimide and 0.27 g of N-hydroxybenzotriazole weresuspended in a mixed solvent comprising 50 ml of acetonitrile and 10 mlof water. 0.54 g ofN-methyl-N-(2-(3,4-dimethoxyphenyl)ethyl)-1,4-diaminobutane was addedthereto and stirred at 60° C. for 30 min. Crystals thus formed werefiltered off and the solvent was distilled off from the filtrate underreduced pressure. The product was purified according to silica gelcolumn chromatography to give 0.50 g of the intended compound in theform of a yellow oil. (Yield: 54%).

NMR (CDCl₃, 400 MHz) δ; 1.5˜1.6 (4H, m), 2.30 (3H, s), 2.4 (2H, m), 2.6(2H, m), 2.7 (2H, m), 3.15 (2H, d, J=7.0 Hz), 3.2˜3.3 (2H, m), 3.84 (3H,s), 3.86 (3H, s), 6.41 (1H, dt, J=16.0 Hz, 7.0 Hz), 6.49 (1H, m), 6.52(1H, d, J=16.0 Hz), 6.7˜6.75 (2H, m), 6.79 (2H, d, J=8 Hz), 7.4˜7.6 (6H,m), 8.23 (2H, m).

EXAMPLE 58(E)-[N-(3-(N'-(2-(3,4-Dimethoxyphenyl)ethyl)-N'-methyl)amino)butyl]-4-[4-(N³-methyl-N² -cyanoquanidino)phenyl]-3-butenamide ##STR168##

0.65 g of (E)-(4-(4-N³ -methyl-N² -cyanoquanidino)phenyl-3-butenoicacid, 0.74 g of3-((N-(2-(3,4-dimethoxyphenyl)ethyl)-N-methyl)amino)butylamine, 0.57 gof N,N'-dicyclohexylcarbodiimide and 0.37 g of N-hydroxybenzotriazolewere added to 9 ml of 50% hydrous acetonitrile and stirred at 70° C. for30 min. A precipitate thus formed was filtered off and the filtrate wasconcentrated under reduced pressure. An aqueous potassium carbonatesolution was added to the residue. The product was extracted withchloroform and the extract was dried over anhydrous potassium carbonate.The solvent was distilled off under reduced pressure and the product waspurified according to silica gel column chromatography (solvent:dichloromethane/methanol/concentrated aqueous ammonia=1000/100/3) togive 0.78 g of the intended compound in the form of a light yellow oil.(Yield: 62%).

NMR (CDCl₃, 400 MHz) δ; 0.96 (3H, d, J=6.4 Hz), 1.49 (1H, m), 1.66 (1H,m), 2.22 (3H, s), 2.55˜2.76 (4H, m), 2.85 (1H, m), 2.86 (3H, d, J=4.8Hz), 3.00 (2H, d, J=7.2 Hz), 3.13 (1H, m), 3.51 (1H, m), 3.83 (3H, s),3.84 (3H, s), 5.00 (1H, br), 6.28 (1H, dt, J=7.2 Hz, 16 Hz), 6.42 (1H,d, J=16 Hz), 6.66 (1H, d, J=2 Hz), 6.69 (1H, dd, J=2 Hz, 8 Hz), 6.79(1H, d, J=8 Hz), 7.11 (2H, d, J=8.4 Hz), 7.19 (1H, br), 7.24 (1H, br),7.35 (2H, d, J=8.4 Hz).

EXAMPLE 59(E)-[N-(3-(N'-(2-(3,5-Dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl]-4-[4-(N³-methyl-N² -carbamoylguanidino)phenyl]-3-butenamide ##STR169##

1.00 g of(E)-[N-(3-(N'-(2-(3,5-dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl]-4-[4-(N³-methyl-N² -cyanoguanidino)phenyl]-3-butenamide was dissolved in a mixedsolvent comprising 10 ml of methanol and 5 ml of chloroform and thesolution was cooled with ice. 2.2 ml of a 4.6M solution of hydrogenchloride in methanol was added thereto and stirred at room temperaturefor 14 h. The solvent was distilled off under reduced pressure. Diluteaqueous ammonia was added to the residue. The product was extracted withchloroform and dried over anhydrous potassium carbonate. The solvent wasdistilled off under reduced pressure. The product was purified accordingto silica gel column chromatography (solvent:dichloromethane/methanol/concentrated aqueous ammonia=1000/100/3) togive 0.82 g of the intended compound in the form of a yellow oil.(Yield: 80%).

NMR (CDCl₃, 400 MHz) δ; 1.05˜1.65 (4H, m), 2.17 (3H, s), 2.42˜ 2.65 (6H,m), 2.83 (3H, d, J=4.4 Hz), 3.01 (2H, d, J=8 Hz), 3.29˜3.38 (2H, m),3.77 (6H, s), 4.78 (1H, br), 6.19 (1H, dt, J=8 Hz, 16 Hz), 6.26 (2H, d,J=2.4 Hz), 6.31 (1H, t, J=2.4 Hz), 6.41 (1H, d, J=16 Hz), 7.12 (2H, d,J=8.4 Hz), 7.21 (1H, br), 7.28 (1H, br), 7.33 (1H, d, J=8.4 Hz).

EXAMPLES 60 TO 71

Compounds described in Examples 60 to 71 were produced according to theprocess described in Example 54.

EXAMPLE 60(E)-[N-(4-(N'-(2-(3,4-Dimethoxyphenyl)ethyl)-N'-methyl)amino)butyl]-4-[5-(1H-imidazol-1-yl)-3-methylthiophen-2-yl]-3-butenamide##STR170##

light yellow oil (yield: 57%).

NMR (CDCl₃, 400 MHz) δ; 1.5˜1.6 (4H, m), 2.21 (3H, s), 2.34 (3H, s),2.4˜2.5 (2H, m), 2.6˜2.7 (2H, m), 2.7˜ 2.8 (2H, m), 3.11 (2H, d, J=7.0Hz), 3.2˜3.3 (2H, m), 3.85 (3H, s), 3.87 (3H, s), 6.00 (1H, dt, J=7.0Hz, 16.0 Hz), 6.48 (1H, m), 6.62 (1H, d, J=16.0 Hz), 6.68 (1H, s), 6.72(1H, br s), 6.73 (1H, dd, J=2.0 Hz, 7.0 Hz), 6.79 (1H, d, J=7.0 Hz),7.14 (1H, m), 7.15 (1H, m), 7.72 (1H, m).

EXAMPLE 61 (E)-[N-(4-(N'-(2-(34-Dimethoxyphenyl)-N'-methyl)amino)butyl]-4-[5-(3-pyridyl)thiophen-2-yl]-3-butenamide##STR171##

yellow oil (yield: 60%).

NMR (CDCl₃, 400 MHz), δ; 1.50˜1.66 (4H, m), 2.38 (3H, s), 2.50˜2.56 (2H,m), 2.63˜2.73 (2H, m), 2.73˜2.83 (2H, m), 3.12 (2H, dd, J=8.0 Hz, 1.0Hz), 3.24˜3.31 (2H, m), 3.84 (3H, s), 3.86 (3H, s), 6.18 (1H, dt, J=16.0Hz, 8.0 Hz), 6.44 (1H, bt, J=5.0 Hz), 6.62 (1H, dt, J=16.0 Hz), 1.0 Hz),6.70˜6.76 (2H, m), 6.78 (1H, d, J=7.0 Hz), 6.72 (1H, d, J=4.0 Hz), 7.21(1H, d, J=4.0 Hz), 7.29 (1H, ddd, J=8.0 Hz, 5.0 Hz, <1.0 Hz), 7.81 (1H,ddd, J=8.0 Hz, 2.0 Hz, <1.0 Hz), 8.49 (1H, dd, J=5.0 Hz, 2.0 Hz), 8.84(1H, dd, J=2.0 Hz, <1.0 Hz).

EXAMPLE 62(E)-[N-(4-(N'-(2-(3,5-Dimethoxyphenyl)ethyl)-N'-methyl)amino)butyl]-4-[5-(3-pyridyl)thiophen-2-yl]-3-butenamide##STR172##

yellow oil (yield: 64%).

NMR (CDCl₃, 400 MHz) δ; 1.5˜1.6 (4H, m), 2.33 (3H, s), 2.45˜2.50 (2H,m), 2.62˜2.70 (2H, m), 2.70˜2.78 (2H, m), 3.11 (2H, dd, J=7.0 Hz, 1.0Hz), 3.23˜3.50 (2H, m), 3.76 (6H, s), 6.18 (1H, dt, J=16.0 Hz, 8.0 Hz),6.30˜6.36 (3H, m), 6.50 (1H, bt, J=4.0 Hz), 6.61 (1H, dt, J=16.0 Hz, 1.0Hz), 6.92 (1H, d, J=4.0 Hz), 7.21 (1H, d, J=4.0 Hz), 7.29 (1H, ddd,J=8.0 Hz, 5.0 Hz, <1.0 Hz), 7.81 (1H, ddd, J=8.0 Hz, 1.5 Hz, <1.0 Hz(),8.49 (1H, dd, J=5.0 Hz, 1.5 Hz), 8.86 (1H, dd, J=1.5 Hz, <1.0 Hz).

EXAMPLE 63(E)-[N-(3-(N'-(2-(3,4-Dimethoxyphenyl)ethyl)-N'-methyl)amino)butyl]-4-[4-(3-pyridyl)phenyl]-3-butenamide##STR173##

light yellow oil (yield: 98%).

NMR (CDCl₃, 400 MHz) δ; 0.93 (3H, d, J=6.4 Hz), 1.48 (1H, m), 1.63 (1H,m), 2.19 (3H, s), 2.51˜2.60 (4H, m), 2.84 (1H, br), 3.06 (2H, d, J=7.2Hz), 3.11 (1H, m), 3.56 (1H, m), 3.82 (3H, s), 3.83 (3H, s), 6.33 (1H,dt, J=7.2 Hz, 15.6 Hz), 6.51 (1H, d, J=15.6 Hz), 6.64 (1H, dd, J=2 Hz, 8Hz), 6.66 (1H, d, J=2 Hz), 6.75 (1H, d, J=8 Hz), 7.26 (1H, br), 7.35(1H, ddd, J=1.6 Hz, 2.4 Hz, 8.4 Hz), 7.45 (2H, d, J=8.4 Hz), 7.51 (2H,d, J=8.4 Hz), 7.83 (1H, ddd, J=0.8 Hz, 4.4 Hz, 8.4 Hz), 8.58 (1H, dd,J=1.6 Hz, 4.4 Hz), 8.83 (1H, dd, J=0.8 Hz, 2.4 Hz).

EXAMPLE 64(E)-[N-(4-(N'-(2-(3,4-Dimethoxyphenyl)ethyl)-N'-methyl)amino)butyl]-4-[4-(N-oxy-3-pyridyl)phenyl]-3-butenamide##STR174##

light yellow oil (yield: 66%).

NMR (CDCl₃, 400 Hz) δ; 1.5˜1.6 (4H, m), 2.30 (3H, s), 2.41˜2.46 (2H, m),2.58˜2.64 (2H, m), 2.70˜2.76 (2H, m), 3.16 (2H, d, J=7.0 Hz), 3.24˜3.30(2H, m), 3.84 (3H, s), 3.86 (3H, s), 6.42 (1H, dt, J=16.0 Hz, 7.0 Hz),6.53 (1H, d, J=16.0 Hz), 6.58 (1H, bt, J=4.5 Hz), 6.70˜6.76 (2H, m),6.79 (1H, d, J=8.5 Hz), 7.30˜7.36 (1H, m), 7.44˜7.48 (5H, m), 8.18 (1H,bd, J=6.5 Hz), 8.44 (1H, br s).

EXAMPLE 65(E)-[N-(4-(N'-(2-(3,4-Dimethoxyphenyl)ethyl)-N'-methyl)amino)butyl]-4-[4-(2-methoxy-5-pyridyl)phenyl]-3-butenamide##STR175##

white solid (yield: 98%).

NMR (CDCl₃, 400 MHz) δ; 1.50˜1.58 (4H, m), 2.31 (3H, s), 2.40˜2.48 (2H,m), 2.56˜2.66 (2H, m), 2.70˜2.80 (2H, m), 3.15 (2H, dd, J=7.0 Hz, 1.0Hz), 3.24˜3.30 (2H, m), 3.83 (3H, s), 3.85 (3H, s), 4.03 (3H, s), 6.34(1H, m), 6.37 (1H, dt, J=16.0 Hz, 7.0 Hz), 6.55 (1H, d, J=16.0 Hz), 6.67(1H, dd, J=8.0 Hz, <1.0 Hz), 6.70˜6.73 (2H, m), 6.77 (1H, d, J=9.0 Hz),7.32 (1H, dd, J=7.5 Hz, <1.0 Hz), 7.44 (2H, d, J=8.5 Hz), 7.61 (1 H, dd,J=8.0 Hz, 7.5 Hz), 8.00 (2H, d, J=8.5 Hz).

EXAMPLE 66(E)-[N-(4-(N'-(2-(3,4-Dimethoxyphenyl)ethyl)-N'-methyl)amino)butyl]-4-[4-(1,2-dihydro-1-methyl-2-oxo-5-pyridyl)phenyl]-3-butenamide##STR176##

light yellow oil (yield: 100%).

NMR (CDCl₃, 400 MHz) δ; 1.53˜1.62 (4H, m), 2.34 (3H, s), 2.46˜2.50 (2H,m), 2.61˜2.68 (2H, m), 2.73˜2.78 (2H, m), 3.15 (2H, d, J=7.0 Hz),3.25˜3.30 (2H, m), 3.62 (3H, s), 3.85 (3H, s), 3.86 (3H, s), 6.36 (1H,dd, J=15.5 Hz, 7.0 Hz), 6.51 (1H d, J=15.5 Hz), 6.52 (1H, m), 6.65 (1H,d, J=9.0 Hz), 6.71˜6.75 (2H, m), 6.79 (1H, d, J=8.5 Hz), 7.34 (2H, d,J=8.5 Hz), 7.40 (2H, d, J=8.5 Hz), 7.50 (1H, d, J=3.0 Hz), 7.62 (1H, dd,J=9.0 Hz, 3.0 Hz).

EXAMPLE 67(E)-[N-(3-(N'-(2-(3,5-Dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl]-4-[4-(N³-ethyl-N² -cyanoguanidino)phenyl]-3-butenamide ##STR177##

light yellow amorphous product (yield: 70%).

NMR (CDCl₃, 400 MHz) δ; 1.13 (3H, t, J=6.8 Hz), 1.59˜1.70 (2H, m), 2.20(3H, s), 2.49˜2.58 (4H, m), 2.60˜2.66 (2H, m), 3.02 (2H, d, J=7.2 Hz),3.26˜3.38 (4H, m), 3.77 (6H, s), 6.24 (2H, d, J=2 Hz), 6.27 (1H, dt,J=7.2 Hz, 16 Hz), 6.32 (1H, t, J=2 Hz), 6.43 (1H, d, J=16 Hz), 7.00 (1H,br), 7.12 (2H, d, J=8.4 Hz), 7.25 (1H, br), 7.39 (2H, d, J=8.4 Hz).

EXAMPLE 68(E)-[N-(3-(N'-(2-(3,5-Dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl]-4-[4-(N³-isopropyl-N² -cyanoguanidino)phenyl]-3-butenamide ##STR178##

light yellow oil (CDCl₃, 400 MHz).

NMR (CDCl₃, 400 MHz) δ; 1.14 (3H, d, J=6.5 Hz), 1.61˜1.72 (2H, m), 2.22(3H, s), 2.51˜2.61 (4H, m), 2.62˜2.68 (2H, m), 3.02 (2H, dd, J=0.8 Hz,7.2 Hz), 3.33˜3.38 (2H, m), 3.78 (6H, s), 4.03 (1H, m), 4.56 (1H, br),6.21˜6.35 (4H, m), 6.44 (1H, dt, J=0.8 Hz, 16 Hz), 6.94 (1H, br), 7.11(2H, d, J=8.4 Hz), 7.24 (1H, br), 7.40 (2H, d, J=8.4 Hz).

EXAMPLE 69(E)-[N-(4-(N'-(2-(3,5-Dimethoxyphenyl)ethyl)-N'-methyl)amino)butyl]-4-[4-(N³-ethyl-N² -cyanoguanidino)phenyl]-3-butenamide ##STR179##

yellow oil (yield: 89%).

NMR (CDCl₃, 400 MHz) δ; 1.13 (3H, t, J=7.2 Hz), 1.52˜1.61 (4H, m), 2.29(3H, s), 2.41˜2.48 (2H, m), 2.61˜2.67 (2H, m), 2.69˜2.76 (2H, m), 3.11(2H, d, J=7.2 Hz), 3.22˜3.29 (2H, m), 3.29˜3.36 (2H, m), 3.78 (6H, s),4.81 (1H, br), 6.30˜6.39 (4H, m), 6.41 (1H, br), 6.49 (1H, d, J=16 Hz),7.00 (1H, br), 7.14 (2H, d, J=8.4 Hz), 7.42 (2H, d, J=8.4 Hz).

EXAMPLE 70(E)-[N-(4-(N'-(2-(3,5-Dimethoxyphenyl)ethyl)-N'-methyl)amino)butyl]-4-[4-(N³-n-propyl-N² -cyanoguanidino)phenyl]-3-butenamide ##STR180##

yellow oil (yield: 75%).

NMR (CDCl₃, 400 MHz) δ; 0.89 (3H, t, J=7.2 Hz), 1.48˜1.60 (6H, m), 2.32(3H, s), 2.43˜2.49 (2H, m), 2.63˜2.69 (2H, m), 2.71˜2.77 (2H, m), 3.12(2H, d, J=6.8 Hz), 3.21˜3.29 (4H, m), 3.78 (6H, s), 4.86 (1H, br),6.29˜6.39 (4H, m), 6.43 (1H, br), 6.49 (1H, d, J=16.4 Hz), 7.06 (1H,br), 7.14 (2H, d, J=8.4 Hz), 7.42 (2H, d, J=8.4 Hz).

EXAMPLE 71(E)-[N-(4-(N'-(2-(3,5-Dimethoxyphenyl)ethyl)-N'-methyl)amino)butyl]-4-[4-(N³-isopropyl-N² -cyanoguanidino)phenyl]-3-butenamide ##STR181##

yellow oil (yield: 54%).

NMR (CDCl₃, 400 MHz) δ; 1.13 (6H, d, J=6.4 Hz), 1.52˜1.60 (4H, m), 2.32(3H, s), 2.43˜2.49 (2H, m), 2.64˜2.69 (2H, m), 2.71˜2.78 (2H, m), 3.12(2H, d, J=7.2 Hz), 3.23˜3.28 (2H, m), 3.78 (6H, s), 4.60 (1H, d, J=5.6Hz), 6.30˜6.39 (4H, m), 6.43 (1H, br), 6.49 (1H, d, J=16 Hz), 7.04 (1H,br), 7.12 (2H, d, J=8.4 Hz), 7.42 (2H, d, J=8.4 Hz).

We claim:
 1. A butenoic acid compound having the formula (I) ##STR182##wherein R¹ represents ##STR183## wherein Ra and Rb independently arehydrogen, nitro, cyano, trifluoromethyl, an alkylsulfonyl, anarylsulfonyl, a halogen or a lower alkylcarbonyl;Z represents O or S or--CH═CH--; R⁶ and R⁷ may be the same or different and represent H, alower alkyl, cycloalkyl or alkyl group; A represents a C₁₋₆ alkylenegroup which may have a lower alkyl or hydroxyl substituted lower alkylgroup bonded to any carbon on said C₁₋₆ alkylene group; J represents agroup represented by the formula ##STR184## wherein R⁸, R⁹ and R¹⁰ arethe same or different and represent a hydrogen, a halogen, a loweralkyl, a lower alkoxy, hydroxyl, nitro, cyano, or trifluoromethyl group,or --NR¹¹ R¹², wherein R¹¹ and R¹² are the same or different andrepresent a hydrogen, a lower alkyl group or an alkanoylamino group; orany two of R⁸, R⁹ and R¹⁰ may join to form an alkylenedioxy group; andn=1 to 6; or a pharmacologically acceptable salt thereof.
 2. Thecompound or salt as claimed in claim 1, in which the compound has theformula (B): ##STR185## wherein Ra and Rb independently are, hydrogen,nitro, cyano, trifluoromethyl, an alkylsulfonyl, an arylsulfonyl, ahalogen or a lower alkylcarbonyl;R⁶ and R⁷ may be the same or differentand represent H, a lower alkyl, cycloalkyl or alkyl group; A is analkylene having 4 to 6 carbon atoms; R⁸, R⁹ and R¹⁰ are the same ordifferent and represent a hydrogen, a halogen, a lower alkyl, a loweralkoxy, hydroxyl, nitro, cyano, or trifluoromethyl group, or --NR¹¹ R¹²,wherein R¹¹ and R¹² are the same or different and represent a hydrogen,a lower alkyl group or an alkanoylamino group; or any two of R⁸, R⁹ andR¹⁰ may join to form an alkylenedioxy group; and n is an integer of 1 to6.
 3. A butenoic acid compound having the formula (I) ##STR186## whereinR¹ represents ##STR187## wherein Ra and Rb independently are hydrogen,nitro, cyano, trifluoromethyl, an alkylsulfonyl, an arylsulfonyl, ahalogen or a lower alkylcarbonyl;R⁶ and R⁷ may be the same or differentand represent H, a lower alkyl, cycloalkyl or alkyl group; A representsa C₁₋₆ alkylene group which may have a lower alkyl or hydroxylsubstituted lower alkyl group bonded to any carbon on said C₁₋₆ alkylenegroup; J represents a group represented by the formula ##STR188##wherein R⁸, R⁹ and R¹⁰ are the same or different and represent ahydrogen, a halogen, a lower alkyl, a lower alkoxy, hydroxyl, nitro,cyano, or trifluoromethyl group, or --NR¹¹ R¹², wherein R¹¹ and R¹² arethe same or different and represent a hydrogen, a lower alkyl group oran alkanoylamino group; or any two of R⁸, R⁹ and R¹⁰ may form analkylenedroxy group; and n=1 to 6; or a pharmacologically acceptablesalt thereof.
 4. The compound or salt as claimed in claim 1, in whichthe compound has the formula (A): ##STR189## wherein, (A), Ra and Rbare, hydrogen, nitro, cyano, trifluoromethyl, an alkylsulfonyl, anarylsulfonyl, a halogen or a lower alkylcarbonyl, Z is vinylene, oxygen,sulfur or azomethyne, R6 and R7 and J are the same as defined in theformula (I), A' is an alkylene having 4 to 6 carbon atoms and n is aninteger of 1 to
 6. 5. The compound or salt as claimed in claim 4, inwhich Ra and Rb are hydrogen, Z is vinylene, R6 and R7 are hydrogen or alower alkyl, A' is an alkylene having 4 carbon atoms, n is 2 and R⁸, R⁹and R¹⁰ are each a lower alkoxy group having 1 to 3 carbon.
 6. Thecompound or salt as claimed in claim 1, which is selected from the groupconsistingof:(E)-N-[4-(N'-(2-(3,5-Dimethoxyphenyl)ethyl)-N'-methyl)amino)butyl]-4-(4-(1H-imidazol-1-yl)phenyl)-3-butenamide(E)-N-[4-((N'-(2-(3,5-Dimethoxyphenyl)ethyl)-N'-methyl)amino)butyl]-4-(4-nitro-1H-imidazol-1-yl)phenyl]-3-butenamide(E)-N-[4-((N'-(2-(3,5-Dimethoxyphenyl)ethyl)-N'-methyl)amino)butyl]-4-(2-(1H-imidazol-1-yl)thiophen-5-yl)-3-butenamide(E)-N-[4-((N'-(2-(3,4-Dimethoxyphenyl)ethyl)-N'-methyl)amino)butyl]-4-(4-(1H-imidazol-1-yl)phenyl)-3-butenamide(E)-N-[4-((N'-(2-(4-Methoxyphenyl)ethyl)-N'-methyl)amino)butyl]-4-(4-(1H-imidazol-1-yl)phenyl)-3-butenamide(E)-N-[4-((N'-(2-(4-Methoxyphenyl(ethyl)-N'-methyl)amino)butyl]-4-(4-(1H-imidazol-1-yl)phenyl)-3-butenamide(E)-N-[4-((N'-(2-(4-Methoxy-3-methylphenyl)ethyl)-N'-methyl)amino)butyl]-4-(4-(1H-imidazol-1-yl)phenyl)-3-butenamide(E)-N-[4-((N'-(2-(4-Nitrophenyl)ethyl)-N'-methyl)amino)butyl]-4-(4-(1H-imidazol-1-yl)phenyl)-3-butenamide;and(E)-N-[4-(2-(3,5-Dimethoxyphenyl)ethyl)-N'-methyl)amino)butyl]-4-(5-(1H-imidazol-1-yl)furan-2-yl]-3-butenamide.7. The compound or salt as claimed in claim 3, in which R1 is imidazolyland A is an alkyl having 4 carbon atoms.
 8. The compound or salt asclaimed in claim 3, in which R1 is imidazolyl, A is an alkyl having 4carbon atoms and J is 3,4-dimethoxyphenyl or 3,5-dimethoxyphenyl.
 9. Thecompound or salt as claimed in claim 3, in which J is3,4-dimethoxyphenyl or 3,5-dimethoxyphenyl.
 10. A pharmacologicalcomposition which comprises a pharmacologically effective amount of thecompound or salt as defined in claim 1 and a pharmacologicallyacceptable carrier.
 11. A pharmacological composition which comprises apharmacologically effective amount of the compound or salt as defined inclaim 3 and a pharmacologically acceptable carrier.
 12. A method fortreating, remitting or ameliorating ischemic heart diseases byadministering a pharmacologically effective amount of the compound orsalt defined in claim 1 to a human being in need thereof.
 13. A methodfor treating, remitting or ameliorating ischemic heart diseases byadministering a pharmacologically effective amount of the compound orsalt defined in claim 3 to a human being in need thereof.